RxPG News : Parkinson's

Rotigotine transdermal system approved for Parkinson's disease in US

Thu, 17 May 2007 01:35:43 PST

( from http://www.rxpgnews.com ) The U.S. Food and Drug Administration (FDA) today announced the approval of Neupro (rotigotine transdermal system), a skin patch designed to treat symptoms of early Parkinson's disease. Rotigotine is a drug not previously approved in the United States. Neupro is the first transdermal patch approved for the treatment of symptoms of Parkinson's disease.

Parkinson's disease, which belongs to a group of conditions called motor system disorders, results from the loss of dopamine-producing brain cells. Rotigotine, a member of the dopamine agonist class of drugs, is delivered continuously through the skin (transdermal) using a silicone-based patch that is replaced every 24 hours. A dopamine agonist works by activating dopamine receptors in the body, mimicking the effect of the neurotransmitter dopamine.

The effectiveness of Neupro was demonstrated in one fixed-dose response study and two flexible-dose studies. The parallel group studies were randomized, double-blinded, and placebo-controlled, and involved 1,154 patients with early Parkinson's disease who were not taking other Parkinson's medications.

The most common side effects for Neupro included skin reactions at the patch site, dizziness, nausea, vomiting, drowsiness and insomnia, most of which are typical of this class of drugs. Other potential safety concerns include sudden onset of sleep while engaged in routine activities such as driving or operating machinery (sleep attacks), hallucinations, and decreased blood pressure on standing up (postural hypotension).

Exercise may lead to improvement in patients with Parkinson's

Tue, 15 May 2007 19:20:20 PST

( from http://www.rxpgnews.com ) A new study from researchers at the Keck School of Medicine of the University of Southern California (USC) shows that treadmill exercises may benefit patients with Parkinson's Disease and those with similar movement disorders.

The study is led by USC neuroscientist Michael Jakowec, Ph.D., assistant professor of neurology and appears in the May 16 issue of the Journal of Neuroscience.

Recent studies have shown that exercise can have beneficial effects in patients with Parkinson's Disease but the underlying reasons haven't been fully explored. This new study using treadmill exercise in animal models looked at the effects of dopamine in motor learning and execution.

Parkinson's Disease is a chronic and degenerative disease that leads to slowness, balance disorders, tremors and difficulty in walking. The disease results from the loss of dopamine-producing nerve cells in the brain. It is critical as a stimulator of motor system nerves in the body. While there is no current cure for the disease, several treatments do offer relief from its symptoms.

This particular study looked at treadmill exercise and its effects between animal models with and without a loss of certain cells that are similar to what a Parkinson's Patient might suffer. Given the importance of dopamine in Parkinson's Disease, the researchers looked at changes in dopamine levels, among other results.

They found that the subjects with cell loss and that exercised indeed had an effect on dopamine levels while normal subjects showed less of a difference in levels.

"Our study shows that the beneficial effects of exercise in Parkinson's Disease may be due to a more efficient use of dopamine, "says Giselle Petzinger, M.D., assistant professor of neurology at the Keck School of Medicine of USC and the study's first author. "Surviving dopamine cells in our animal models- made to simulate what Parkinson's patients suffer with- subjected to intensive treadmill exercise appear to work harder."

Studies with John Walsh, Ph.D., associate professor at the USC Andrus Gerontology Center and a co-investigator of the study, showed that these cells release greater amounts of dopamine and decrease the rate of its removal from the synapse compared to neurons in subjects that do not undergo exercise.

The findings suggest that the benefits of treadmill exercise on motor performance may be accompanied by changes in dopamine neurotransmission that are different in the injured subjects compared to the non-injured.

"Studies in our animal model of Parkinson's disease support the fact that exercise is beneficial for patients with Parkinson's," says Jakowec. "Exercise may help the injured brain to work more efficiently by allowing the remaining dopamine producing neurons to work harder and in doing so may promote stronger connections in the brain."

Further studies will investigate if beneficial effects of exercise have long-term effect on the injured brain, identifying the molecular links between exercise and the brain, and to better understand the molecular mechanisms within neurons that lead to these changes.

Coenzyme Q10 does not improve Parkinson's disease symptoms

Mon, 14 May 2007 20:38:33 PST

( from http://www.rxpgnews.com ) Small doses of the antioxidant coenzyme Q10 appear to increase blood levels of this naturally occurring compound in patients with Parkinson's disease, but does not improve Parkinson's disease symptoms, according to an article posted online today that will appear in the July 2007 print issue of Archives of Neurology, one of the JAMA/Archives journals.

Parkinson's disease is a neurodegenerative disorder characterized by tremors and difficulty with walking or other movements. The biological mechanisms underlying the condition are not fully understood, but researchers suspect a malfunction of the mitochondria, parts of the cells that help convert food to energy, according to background information in the article. Coenzyme (CoQ10), an antioxidant sold as a dietary supplement, is also involved in mitochondrial processes. "Because of these functions, CoQ10 has attracted attention concerning neuroprotective actions in neurodegenerative disorders linked to mitochondrial defects or oxidative [oxygen-related] stress, such as Huntington's disease and Parkinson's disease," the authors write. Previous studies indicate that high doses of CoQ10 (1,200 milligrams) may slow the deterioration associated with Parkinson's disease.

Alexander Storch, M.D., of the Technical University of Dresden, Germany, and colleagues conducted a randomized clinical trial of a 300-milligram dose of CoQ10 in 131 patients with Parkinson's disease who did not have changes in motor functions and were on stable treatment for their condition. Those assigned to the treatment group took 100 milligrams of CoQ10 three times daily for three months, followed by a two-month "washout" period. The researchers assessed Parkinson's disease symptoms before treatment began, each month during treatment and again after the washout period. Blood tests were performed at the beginning of the study, after three months of treatment and after the washout period.

A total of 106 patients completed the full three months of the studyâ55 in the CoQ10 group and 51 in the placebo group. The compound was well tolerated overall, and the percentage of patients who experienced adverse effectsâincluding viral infection, diarrhea and hearing lossâdid not differ between the two groups. Blood levels of CoQ10 increased in the treatment group from an average of 0.99 milligrams per liter to an average of 4.46 milligrams per liter after three months.

"Although we demonstrated a significant increase in plasma levels of CoQ10 toward levels observed with high doses of standard CoQ10 formulations in Parkinson's disease and other disorders, our study failed to show improvement of Parkinson's disease symptoms and did not meet its primary or secondary end points," which were changes on scales that measured Parkinson's disease symptoms and their effects on physical and mental functioning, the authors write. "Our study further demonstrated that 300 milligrams per day of nanoparticular CoQ10 is safe and well tolerated in patients with Parkinson's disease already taking various antiparkinsonian medications."

"Since we did not find symptomatic effects of CoQ10 in Parkinson's disease, our study does not support the hypothesis that restoring the impaired energy metabolism of the diseased dopaminergic neurons leads to symptomatic benefits in Parkinson's disease," the authors conclude. "Future studies will need to explore the protective effects of CoQ10 at the highest effective dose (equivalent to about 2,400 milligrams per day of a standard formulation) over a long treatment period and in a large cohort of patients both sufficient to clearly define the protective potential of this compound in Parkinson's disease."

UCLA researchers discover link between Parkinson's and narcolepsy

Fri, 11 May 2007 11:15:29 PST

( from http://www.rxpgnews.com ) Parkinson's disease is well-known for its progression of motor disorders: stiffness, slowness, tremors, difficulties walking and talking. Less well known is that Parkinson's shares other symptoms with narcolepsy, a sleep disorder characterized by sudden and uncontrollable episodes of deep sleep, severe fatigue and general sleep disorder.

Now a team of UCLA and Veterans Affairs researchers think they know why â the two disorders share something in common: Parkinson's disease patients have severe damage to the same small group of neurons whose loss causes narcolepsy. The findings suggest a different clinical course of treatment for people suffering with Parkinson's that may ameliorate their sleep symptoms.

In their report (currently online) in the June issue of the journal Brain, Jerry Siegel, professor of psychiatry and biobehavioral sciences at the Semel Institute for Neuroscience and Human Behavior at UCLA, assistant resident neurobiologist Thomas C. Thannickal and associate research physiologist Yuan-Yang Lai have determined that Parkinson's disease patients have a loss of up to 60 percent of brain cells containing the peptide hypocretin. In 2000, this same group of UCLA researchers first identified the cause of narcolepsy as a loss of hypocretin, thought to be important in regulating the sleep cycle. This latest research points to a common cause for the sleep disorders associated with these two diseases and suggests that treatment of Parkinson's disease patients with hypocretin or hypocretin analogs may reverse these symptoms.

More than 1 million people in the U.S. have been diagnosed with Parkinson's disease, and approximately 20 million worldwide. (The percentage of those afflicted increases with age.) Narcolepsy affects approximately one in 2,000 individuals â about 150,000 in the United States and 3 million worldwide. Its main symptoms are sleep attacks, nighttime sleeplessness and cataplexy, the sudden loss of skeletal muscle tone without loss of consciousness; that is, although the person cannot talk or move, they are otherwise in a state of high alertness, feeling, hearing and remembering everything that is going on around them.

"When we think of Parkinson's, the first thing that comes to mind are the motor disorders associated with it," said Siegel, who is also chief of neurobiology research at the Sepulveda Veterans Affairs Medical Center in Mission Hills, Calif. "But sleep disruption is a major problem in Parkinson's, often more disturbing than its motor symptoms. And most Parkinson's patients have daytime sleep attacks that resemble narcoleptic sleep attacks."

In fact, said Siegel, Parkinson's disease is often preceded and accompanied by daytime sleep attacks, nocturnal insomnia, REM sleep disorder, hallucinations and depression. All of these symptoms are also present in narcolepsy.

In the study, the researchers examined 16 human brains from cadavers â five from normal adults and 11 in various stages of Parkinson's â and found an increasing loss of hypocretin cells (Hcrt) with disease progression. In fact, said Siegel, the later stages of Parkinson's were "characterized by a massive loss of the Hcrt neurons. That leads us to believe the loss of Hcrt cells may be a cause of the narcolepsy-like symptoms of [Parkinson's] and may be ameliorated by treatments aimed at reversing the Hcrt deficit."

Enhancing activity of marijuana-like chemicals in brain may treat Parkinson's Disease

Thu, 08 Feb 2007 03:28:28 PST

( from http://www.rxpgnews.com )

The study reports that endocannabinoids, naturally occurring chemicals found in the brain that are similar to the active compounds in marijuana and hashish, helped trigger a dramatic improvement in mice with a condition similar to Parkinson's.

Marijuana-like chemicals in the brain may point to a treatment for the debilitating condition of Parkinson's disease. In a study to be published in the Feb. 8 issue of Nature, researchers from the Stanford University School of Medicine report that endocannabinoids, naturally occurring chemicals found in the brain that are similar to the active compounds in marijuana and hashish, helped trigger a dramatic improvement in mice with a condition similar to Parkinson's.

"This study points to a potentially new kind of therapy for Parkinson's disease," said senior author Robert Malenka, MD, PhD, the Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences. "Of course, it is a long, long way to go before this will be tested in humans, but nonetheless, we have identified a new way of potentially manipulating the circuits that are malfunctioning in this disease."

Malenka and postdoctoral scholar Anatol Kreitzer, PhD, the study's lead author, combined a drug already used to treat Parkinson's disease with an experimental compound that can boost the level of endocannabinoids in the brain. When they used the combination in mice with a condition like Parkinson's, the mice went from being frozen in place to moving around freely in 15 minutes. "They were basically normal," Kreitzer said.

But Kreitzer and Malenka cautioned that their findings don't mean smoking marijuana could be therapeutic for Parkinson's disease.

"It turns out the receptors for cannabinoids are all over the brain, but they are not always activated by the naturally occurring endocannabinoids," said Malenka. The treatment used on the mice involves enhancing the activity of the chemicals where they occur naturally in the brain. "That is a really important difference, and it is why we think our manipulation of the chemicals is really different from smoking marijuana."

The researchers began their study by focusing on a region of the brain known as the striatum. They were interested in that region because it has been implicated in a range of brain disorders, including Parkinson's, depression, obsessive-compulsive disorder and addiction.

The activity of neurons in the striatum relies on the chemical dopamine. A shortage of dopamine in the striatum can lead to Parkinson's disease, in which a person loses the ability to execute smooth motions, progressing to muscle rigidity, tremors and sometimes complete loss of movement. The condition affects 1.5 million Americans, according to the National Parkinson Foundation.

"It turns out that the striatum is much more complicated than imagined," said Malenka. The striatum consists of several different cell types that are virtually indistinguishable under the microscope. To uncover the individual contributions of the cell types, Malenka and Kreitzer used genetically modified mice in which the various cell types were labeled with a fluorescent protein that glows vivid green under a microscope. Having an unequivocal way to identify the cells allowed them to tease apart the functions of the different cell types.

Malenka's lab has long studied how the communication between different neurons is modified by experience and disease. In their examination of two types of mouse striatum cells, Kreitzer and Malenka found that a particular form of adaptation occurs in one cell type but not in the other.

Malenka said this discovery was exciting because no one had determined whether there were functional differences between the various cell types. Their study indicated that the two types of cells formed complementary circuits in the brain.

One of the circuits is thought to be involved in activating motion, while the other is thought to be involved in restraining unwanted movement. "These two circuits are critically involved in a push-pull to select the appropriate movement to perform and to inhibit the other," said Kreitzer.

Dopamine appears to modulate these two circuits in opposite ways. When dopamine is depleted, it is thought that the pathway responsible for inhibiting movement becomes overly activated - leading to the difficulty of initiating motion, the hallmark of Parkinson's disease.

Current treatment for Parkinson's includes drugs that stimulate or mimic dopamine. It turns out that the neurons Kreitzer identified as inhibiting motion had a type of dopamine receptor on them that the other cells didn't. The researchers tested a drug called quinpirole, which mimics dopamine, in mice with a condition similar to human Parkinson's disease, resulting in a small improvement in the mice.

"That was sort of expected," said Malenka. "The cool new finding came when we thought to use drugs that boost the activity of endocannabinoids." Based on prior knowledge of endocannabinoids and dopamine, they speculated that the two chemicals were working in concert to keep the inhibitory pathway in check.

When they added a drug that slows the enzymatic breakdown of endocannabinoids in the brain - URB597, being developed by Kadmus Pharmaceuticals in Irvine, Calif. - the results were striking.

"The dopamine drug alone did a little bit but it wasn't great, and the drug that targeted the enzyme that degrades endocannabinoids basically did nothing alone," Kreitzer said. "But when we gave the two together, the animals really improved dramatically."

Parkinson’s Approach With Stem Cells A Promising First Step

Mon, 04 Dec 2006 11:03:44 PST

( from http://www.rxpgnews.com ) Brain cells derived from human embryonic stem cells improved the condition of rats with Parkinson’s-like symptoms dramatically, but the treatment caused a significant problem – the appearance of brain tumors – that scientists are now working to solve.

The work was reported by neurologist Steven Goldman, M.D., Ph.D., professor of Neurology at the University of Rochester Medical Center and chief of its Division of Cell and Gene Therapy, and Neeta Roy, Ph.D., assistant professor of Neurology at Cornell’s Weill Medical College.

“The results are a real cause for optimism,” said Goldman. “These animals with severe Parkinson’s symptoms had a dramatically improved outcome after treatment. Now we have a new problem to work on, how to achieve the same benefit without creating tumors. But we expect to be able to solve this problem within the next year or two, using new approaches to cell sorting that we’ve been developing.”

“All in all, this is the way medical discoveries move forward: One step at a time.”

Goldman has spent much of his career creating ways to isolate stem cells, discovering the molecular signals that help determine what specific types of cells they become, and then re-creating those signals to direct the cells’ development. It’s the versatility of stem cells that make them so attractive. If scientists like Goldman are successful directing their development, such cells could provide a ready source of cells custom made to treat a given disease – for instance, myelin-producing cells for multiple sclerosis, or the specific types of cells that die in patients with Parkinson’s or Huntington’s diseases.

In the experiment reported in Nature Medicine, Goldman, Roy and colleagues set out to grow brain cells called neurons that produce dopamine, a crucial brain chemical lacking in patients with Parkinson’s. They began by isolating human embryonic stem cells, then using genes such as “sonic hedgehog” and fibroblast growth factor 8 that make chemicals in the normal brain environment. Such signals are the body’s natural way of directing stem cells to develop into the specific cells needed.

Past attempts at using stems cells to make this type of neuron had achieved modest success, but only relatively small numbers could be produced in tissue culture. To improve upon this, Roy and Goldman attempted to re-create the natural environment of the developing brain as much as possible, so it would seem to the stem cells that they were developing in the part of the brain where dopamine neurons are normally made. The team did so by raising the cells together with brain cells known as astrocytes, which had come from the same brain region. These cells have long been known to play a crucial role nourishing neurons.

The result was that more than two-thirds of the stem cells developed into precisely the type of cell needed to treat Parkinson’s disease – dopamine-producing neurons. That percentage is far higher than any previous experiment had achieved.

The team then injected the cells into the brains of rats with Parkinson’s-like symptoms, and watched for 10 weeks. While rats with the disorder walked in circles when prompted to move, as if they were chasing their tails, rats transplanted with the new cells recovered normal function and eventually stopped walking in circles. By eight weeks after treatment, the tail-chasing behavior ended completely, and they were walking and running normally.

Yet when the brains of the animals were examined, the team found tumors within the brain grafts. Goldman said the tumors sprang from stem cells that had started on the road to becoming neurons, but then stalled in their development and grew out of control. The team is working on ways to filter out those cells, to reap the benefits while avoiding the side effects of the approach.

“The appearance of tumors was disappointing, but not surprising,” said Goldman. “The goals of this experiment were to create a population of cells that had many more dopamine neurons than previous attempts yielded, and to measure whether a group of cells with so many of these neurons would yield real-life benefits in terms of behavior. We accomplished both tasks. The cells improved the disease symptoms dramatically, beyond what we expected.

“In this first attempt of the technology, we did not attempt to try to absolutely purify the cell population that was transplanted – thus the brain tumors. The experiment confirmed that we need to have an absolutely pure cell population, and we are working on ways to do that.”

The work was supported by the National Institute of Neurological Disorders and Stroke, and the Michael J. Fox Foundation. Other authors of the paper, all at Cornell, are Carine Cleren, Shashi Singh, Lichuan Yang, and M. Flint Beal.

Laser probe of a brain pigment's anatomy may offer insight into Parkinson's disease

Tue, 26 Sep 2006 23:14:37 PST

( from http://www.rxpgnews.com ) In a finding that may offer clues about Parkinson's disease, a team led by Duke University researchers used a sophisticated laser system to gain evidence that a dark brown pigment that accumulates in people's brains consists of layers of two other pigments commonly found in hair.

Other scientists previously had determined via chemical analysis that the dark pigment, called neuromelanin, is composed of the two pigments: eumelanin, found in black-haired people, and pheomelanin, found in redheads. But how those pigments are arranged structurally remained unknown -- and this structuring may prove to be of critical importance, according to the researchers.

In addition, in 2005 a Duke team that included some of the same scientists involved in the current study reported using the laser system to establish that pheomelanin is chemically disposed to activate oxygen while eumelanin is not. Oxygen activation is suspected to play a role in the neurogenic cascade of events behind Parkinson's disease.

In the new report, investigators from Duke, North Carolina State University and the Institute of Biomedical Technologies in Segrate, Italy, outlined evidence that neuromelanins isolated from human brains have cores of oxygen-activating pheomelanin covered by a protective surface of eumelanin.

"This is the first piece of morphological data about how these pigments are constructed," said study leader John Simon, the George B. Geller Professor of chemistry at Duke.

The findings "should stimulate renewed interest in the roles of neuromelanin in the pathogenesis of Parkinson's disease, the second most prevalent neurodegenerative disorder," Shosuke Ito, a chemist at Japan's Fujita Health University School of Health Sciences, wrote in a companion commentary published in the journal.

According to the team's report, whose first author is Simon's graduate student, William Bush, neuromelanin granules begin appearing in human brains between ages 3 and 5, and their concentrations increase steadily thereafter.

However, neuromelanin levels drop precipitously in the brains of Parkinson's patients, who also experience a death of brain cells that are darkly pigmented and an increase in brain tissue concentrations of the metal iron.

Brain cells that produce dopamine, a key neurotransmitter disrupted in Parkinson's disease, experience high levels of oxidation as that dopamine is made, the researchers noted.

Scientists have hypothesized that brain cells synthesize neuromelanin to serve as a defense mechanism against high oxidation stress, the team's report said.

Neuromelanin's layered granular structure could help protect brain cells from damage in several ways, Ito wrote in his commentary.

Having eumelanin at their surfaces would protect the granules with a pigment known to efficiently bind iron and other molecules that could otherwise play a role in oxidative damage. If the underlying core of pheomelanin were instead positioned at the surface, "the neuro-protective role of neuromelanin would not be expected," Ito added.

However, eumelanin is limited in how much iron it can take up, and other scientists have proposed that iron over-saturation at the granules' surfaces could contribute to the high levels of the metal in the brains of Parkinson's victims.

"Increased oxidative stress under such conditions could result in degradation of the eumelanic surface of neuromelanin," Ito wrote. That could expose a pheomelanin core "that is not only ineffective in iron-binding, but also behaves as a pro-oxidant itself," he added.

"Once these neuromelanin granules start getting chewed into, an environment is created that is much more pro-oxidation," Simon said. "As pigment starts to get eroded, you can imagine how oxidative stress could be increased in multiple ways."

In the study, which Ito called "sophisticated," the researchers used a special laser device that makes light with electrons that have been freed from their usual bondage to atoms. Housed in a large bay in the Duke University Free Electron Laser Laboratory, the device can be "tuned" step-by-step to produce light at a variety of different wavelengths, with each wavelength probing different energy regions in target molecules.

The team also used a device called a photoelectron emission microscope to resolve individual neuromelanin granules and distinguish between the two pigment types.

Using these devices in combination, the researchers could pinpoint the "oxidation potentials" of molecules coating the surfaces of neuromelanin granules. Oxidation potentials measure how likely given chemicals are to activate oxygen by giving up electrons. Activated oxygen can produce compounds called radicals that can stress cells.

The team found that oxidation potentials of molecules at the surfaces approximated those found in black hair pigments in the 2005 study. "That meant it was eumelanin, which is pretty antioxidant," Simon said.

The laser beams could not penetrate beneath the granules' surfaces to record oxygen potentials nearer their cores. But previous chemical analyses by other researchers had established that neuromelanin is a mixture of both red and black hair pigments. So, the new finding suggests "a structural motif, with pheomelanin at the core and eumelanin at the surface," the team reported.

"Something special is happening, where the red pigment is getting encased in the black," Simon said. "So the red, being fairly pro-oxidant, is being encased in this antioxidant pigment."

Simon's group could only deduce the probable structure of neuromelanin, rather than measure it directly, because scientists have so far been unable to synthesize the pigment from chemical building blocks in a form that duplicates the natural version, he said.

"No one knew how to test or probe these things," Simon said. "And I can't overestimate how difficult it was to get materials to test." His group worked with small amounts of autopsied brain tissues provided by a research group led by Luigi Zecca at the Italian Institute of Biomedical Technologies.

Novel blood test for early detection of Parkinson's, receives national recognition

Fri, 01 Sep 2006 17:28:37 PST

( from http://www.rxpgnews.com ) The research of Dr Kay Double, an NHMRC Senior Research Fellow at the Prince of Wales Medical Research Institute, has received the nation's highest commendation through her inclusion in the NHMRC's 2006 "10 of the Best" booklet.

This national publication will be launched by The Minister for Health and Ageing, Tony Abbott at 10am, Friday 1 September in the Scientia Gallery, University of New South Wales.

Dr Double's research into Parkinson's disease looks at the function of neuromelanin, a pigment unique to human brains. In the brain cells of a person with Parkinson's disease, this pigment disappears. Based on her findings, Dr Double and her team have developed a new blood test which will provide early detection for the loss of neuromelanin and this may predict the onset of Parkinson's.

Dr Double's work investigated the vulnerability of the pigment in a Parkinson's disease brain, how it occurs in a healthy brain, why these changes occurred and the consequences of changes for the survival of the brain cells.

"We found that the pigment in the healthy brain protects the cells from free radical-damaging molecules and other toxins," she said, "but in the Parkinson's diseased brain, the pigment is changed so that instead of protecting the cells, it becomes toxic itself.

"Our research indicates that increased amounts of iron bound to the pigment cause the cells to be damaged and die."

"This research is significant it has allowed us to design a new blood test for the onset of Parkinson's disease. It has also highlighted the potential to develop new treatments to slow down, or even stop altogether, brain cell death," concluded Dr Double.

The blood test, currently being commercialised, will not only provide early detection but also correct diagnosis of Parkinson's disease. At the moment, Parkinson's disease can be diagnosed only after signs such as slowness, stiffness and tremor appear.

The Institute's Executive Director, Prof Peter Schofield said," Kay's outstanding research, conducted at the Institute over the past five years, validates our mission to conduct world-class medical research to cure human disease, improve quality of life, and thus create a legacy for the future. This recognition by the NHMRC is a direct reflection of her exceptional ability in the research arena."

Dr Double has been awarded a NHMRC Senior Research Fellowship to continue her research into the causes, diagnosis and treatments of Parkinson's disease.

New genetic model for Parkinson's disease

Mon, 31 Jul 2006 11:28:37 PST

( from http://www.rxpgnews.com ) Researchers at the Karolinska Institute in Sweden are homing in on mechanisms that may explain one set of causes for Parkinson's disease. In mice they have mimicked disturbances of mitochondria thought to be one cause of disease. By genetic means the disturbance of mitochondria - the energy factories of cells - were directed to those nerve cells that produce the transmitter substance dopamine and that die in Parkinson's disease.

"The course of disease in these mice is strikingly similar to human disease", says Dr. Lars Olson.

In the mouse model generated by the research team, a gene called TFAM is automatically deleted from the genome in dopamine nerve cells only. Without TFAM, mitochondria cannot function normally. The so called respiratory chain is compromised and energy production decreases severely in the dopamine cells.

The new mice are born healthy from healthy but genetically modified parents and will develop spontaneous disease. Previous studies in the field have been based on researchers delivering neurotoxic substances to kill the dopamine neurons. In the new mice, however, mice develop disease slowly in adulthood, like humans with Parkinson's disease, which may facilitate research aimed at finding novel medical treatments and other therapies.

"We see that the dopamine producing nerve cells in the brain stem slowly degenerate", says Dr. Nils-Göran Larsson. "In the microscope we can see that the mitochondria are swollen and that aggregates of a protein, probably alpha-synuclein starts to accumulate in the nerve cell bodies. Inclusions of alpha-synuclein-rich so called Lewy bodies is typical for the human disease."

The causes of Parkinson's disease have long remained a mystery. Genes and environment are both implicated, but recently there has been an increased focus on the roles of genetic factors. It has been found that mutations in a number of genes can lead directly to disease, while other mutations may be susceptibility factors, so that carriers have an increased risk of becoming ill. A common denominator for some of the implicated genes is their suggested role for the normal functioning of mitochondria.

"Like patients, the mice can be treated with levo-Dopa, a precursor of the lost substance dopamine", says Dr. Nils-Göran Larsson. "The course of the disease as well as the brain changes in this mouse are more similar to Parkinson's disease than most other models. This supports the notion that genetic risk factors are important."

"Like in patients, the dopamine nerve cells in the new mouse model die in a specific order", says Dr. Lars Olson. "We hope the mouse will help us understand why certain dopamine nerve cells are more sensitive than others, so that we can develop drugs that delay, ore even stop the nerve cell death."

Expertise In Brain Stimulation Therapy May Improve Outcomes in Parkinson's Disease

Wed, 12 Jul 2006 05:40:37 PST

( from http://www.rxpgnews.com ) Patients with Parkinson's disease who are undergoing a treatment known as deep brain stimulation may benefit from the direct involvement of a neurologist with expertise both in movement disorders and in deep brain stimulation, according to an article posted online today that will appear in the September 2006 print issue of the Archives of Neurology, one of the JAMA/Archives journals.

Deep brain stimulation is a surgical procedure that involves implanting electrodes into the brain to electronically stimulate areas that control movement, treating Parkinson's disease symptoms such as tremor, stiffness and problems walking. It is the most effective surgical treatment for advanced cases of Parkinson's disease. Deep brain stimulation involves intensive patient management, including adjustments of electrical currents and medication dosages as a patient's condition changes. Many medical centers in North America delegate these responsibilities to personnel who do not have extensive experience in Parkinson's disease care, such as surgical nurses, fellows or neurophysiologists, according to information in the article.

Elena Moro, M.D., Ph.D., and colleagues at University Health Network, University of Toronto, Ontario, studied whether the outcomes resulting from deep brain stimulation could be improved with the direct involvement of a neurologist with specific expertise both in the treatment of movement disorders in general and in deep brain stimulation in particular. Forty-four consecutive patients at the hospital who had already been receiving regular deep brain stimulation treatments for an average of 3.5 years underwent evaluation by such a neurologist-in other words, the neurologist changed the electric stimulation settings during the procedure and also adjusted the medications that patients received afterward. The patients underwent assessments for Parkinson's disease symptoms before and after their reprogrammed treatment, with following assessments at an average of 5 months (range 1 hour to 14 months) after the reprogramming.

Of the 44 patients, 24 (54.6 percent) showed additional improvement in their Parkinson's disease symptoms; 16 (36.4 percent) were unchanged; and four (9.1 percent) worsened. The patients who did improve experienced fewer tremors and less rigidity and bradykinesia (slowness of movement) and also had reductions in their medication dosages. The four patients who worsened had more speech and gait problems and were returned to their original settings.

"Further improvement of parkinsonian signs can be achieved in the majority of patients even after long-term stable stimulation," the authors conclude. "Improved patient outcomes from subthalamic nucleus deep brain stimulation are obtained when postoperative care is personally managed by a neurologist expert in movement disorders and deep brain stimulation who is directly responsible for stimulation programming and simultaneous drug adjustments based on observed clinical responses to changing stimulation parameters."

Pesticide Dieldrin Linked to Increased Risk of Parkinson's Disease

Fri, 07 Jul 2006 13:09:37 PST

( from http://www.rxpgnews.com ) A team of Emory University researchers has found a connection in laboratory mice between developmental exposure to the pesticide dieldrin (now banned from use) during gestation and lactation and an increased risk of developing Parkinsons disease (PD). The findings are significant because most studies aimed at determining the disease process in PD have been focused on events occurring during adulthood, not during developmental stages.

The pesticide dieldrin was banned for most uses by the Environmental Protection Agency in 1974, then totally banned in 1987, according to the researchers. Dieldrin was most commonly used for insect control in crops and for termite control in home foundations. "While many pesticides have been banned from use today, they still remain in the soil and can take decades to break down, as in the case of dieldrin," says Gary Miller, PhD, neurotoxicologist, researcher in Emory's Center for Neurodegenerative Disease and associate professor in the Department of Environmental and Occupational Health, Rollins School of Public Health at Emory. "Because of dieldrin's lingering effects, our research focuses on the role of the environment and its effects on PD." Dr. Miller is the senior author on this paper.

"Although most people are diagnosed in mid- to late-life with Parkinson's, experimental evidence suggests that neurodegeneration begins long before clinical diagnosis of PD," says Dr. Miller. "Recent research has led to the idea that the etiology of a number of diseases may result from alterations occurring during development. Therefore, we decided to examine whether developmental exposure to dieldrin causes persistent changes to the dopaminergic system and whether these changes can result in increased susceptibility to Parkinson's."

Parkinson's disease is considered a disease of aging, occurring when a group of cells in an area of the brain called the substantia nigra begin to malfunction and die. These cells produce a chemical called dopamine, a neurotransmitter or chemical messenger, that sends information to the parts of the brain that control movement and coordination. When a person has Parkinson's disease, his or her dopamine-producing cells begin to die, leaving that person incapable of initiating and controlling movements in a normal way.

In the Emory study, the researchers administered 0.3 mg/kg, 1 mg/kg, 3 mg/kg of dieldrin or no dieldrin (placebo) every three days to pregnant mice throughout gestation and lactation.

"Through analysis of brain samples, we found the pesticide does not directly kill the dopamine neurons, but instead alters the dopamine neuron homeostasis or equilibrium to cause increased vulnerability to a parkinsonism-inducing toxin," Dr. Miller explains. The study also found the enhanced vulnerability affected male rodent offspring more so than female rodent offspring. The finding is consistent with that observed in the human population affected by PD, in that Parkinson's affects more men than women.

"We also noted that exposure to dieldrin during critical periods of development may lead to the imprinting of genes that regulate the proper formation and maintenance of function of the dopamine system," says Jason Richardson, PhD, co-author and postdoctoral fellow in the Miller laboratory. "This alteration may induce a silent state of dopamine dysfunction and an increased vulnerability of dopamine neurons later in life."

"The results from this study provide a potential molecular mechanism responsible for the association between dieldrin exposure and increased risk of PD and suggests that greater attention should be focused on the role of early life exposures and the development of PD," says Dr. Miller.

ER trafficking defect caused by alpha-synuclein accumulation implicated in Parkinson's

Tue, 27 Jun 2006 02:11:37 PST

( from http://www.rxpgnews.com ) Howard Hughes Medical Institute researchers have pinpointed defects in a critical cellular pathway that can lead to the death of dopamine-producing nerve cells and ultimately symptoms of Parkinson's disease. They have also used several animal models of the disease to identify a new way to rescue dying neurons.

According to the researchers, the findings offer a promising opportunity for developing new drugs to treat the underlying causes of Parkinson's disease and related neurodegenerative disorders.

The research team, which included Howard Hughes Medical Institute investigators Susan L. Lindquist and Nancy M. Bonini, published their findings on June 22, 2006, in Science Express, which provides electronic publication of selected Science papers in advance of print. Lindquist is at the Whitehead Institute for Biomedical Research and Bonini is at the University of Pennsylvania. Other co-authors were from Purdue University, the University of Alabama, Medical College of Georgia and New York University.

The researchers' began their experiments seeking to clarify the role of the protein alpha-synuclein in Parkinson's disease. It had long been known that abnormalities in alpha-synuclein could cause a lethal buildup of the protein in neurons. Researchers also knew that accumulation of alpha-synuclein caused neurodegeneration in animal models of Parkinson's disease, but little was known about alpha-synuclein's normal cellular function or how it contributed to disease. One major problem facing researchers, Lindquist said, was that alpha-synuclein accumulation causes a range of abnormalities, and it was not possible to sort out which were causes and which were effects in Parkinson's disease pathology.

However, Lindquist's team developed a technique to switch on overproduction of alpha-synuclein in yeast, so they could determine which abnormalities arose earliest in the pathological process. Those experiments by Cooper revealed that an important early defect affected the machinery that transports proteins between two major cellular organelles the endoplasmic reticulum (ER) and the Golgi apparatus. Lindquist and her colleagues had conducted a genetic screen in yeast to discover genes whose activity affected the toxicity of alpha-synuclein. That study showed that genes enhancing ER-to-Golgi trafficking prevented alpha-synuclein toxicity. In particular, they found that one protein, called Ypt1p, which is involved in regulating trafficking could also be switched on to suppress alpha-synuclein toxicity in yeast cells.

Our findings indicated that this ER-to-Golgi trafficking pathway is intimately coupled to the pathology, although in humans there are likely others involved as well, given how many genes we found that modified alpha-synuclein toxicity, said Lindquist. But these findings were so persuasive that we decided we needed to test whether enhancing Ypt1p activity would suppress alpha-synuclein toxicity in animal models of the disease. The researchers next studied whether enhancing activity of the mammalian Ytp1p counterpart, called Rab1, suppressed alpha-synuclein toxicity in the fruitfly Drosophila, the roundworm C. elegans and in cultures of rat neurons. Bonini and her colleagues tested the effect in fruitflies; co-author Guy Caldwell and his colleagues at the University of Alabama performed the tests in roundworms; and co-author Jean-Christophe Roche and his colleagues at Purdue performed the tests in rat neurons. Caldwell is also coordinator of HHMI's Undergraduate Research Intern Program at the University of Alabama.

All saw significant suppression of toxicity; although none saw complete suppression, which confirms our yeast studies showing that other pathways are affected by alpha-synuclein accumulation. Lindquist also said the findings give important clues to why dopamine-producing neurons in the brain are the most vulnerable neurons to toxic alpha-synuclein accumulation. The death of such neurons reduces brain dopamine levels, causing the tremors and other symptoms of Parkinson's disease. Dopamine is one of many types of neurotransmitter chemical signals that one neuron launches at its neighbor to trigger a nerve impulse.

Lindquist and her colleagues believe their findings will guide the search for new drugs that suppress alpha-synuclein toxicity by enhancing the machinery of ER-to-Golgi transport. Thus, she said, they have already conducted a screen of 150,000 compounds for those with therapeutic potential.

We have found compounds that reverse alpha-synuclein toxicity, and we plan to publish those results soon, she said. Current treatments for Parkinson's disease do not aim at protecting the dopamine-producing neurons themselves. Rather, the treatments seek to restore dopamine levels in the brain or to treat symptoms of the disease.

Bonini added that the research team's findings illustrate the power of animal models in revealing insight into Parkinson's disease. These results highlight the value and importance of very simple model organisms in studying these disorders, she said. For example, yeast is only a single cell, not even a neuron, and yet it can reveal proteins that modify the toxicity of alpha-synuclein. And in flies, it is possible to study the effects of these proteins on alpha-synuclein toxicity in dopaminergic neurons.

Pesticides exposure associated with Parkinson's disease

Tue, 27 Jun 2006 01:49:37 PST

( from http://www.rxpgnews.com ) In the first large-scale, prospective study to examine possible links between chronic, low-dose exposure to pesticides and Parkinson's disease (PD), researchers at the Harvard School of Public Health (HSPH) have shown that individuals reporting exposure to pesticides had a 70 percent higher incidence of PD than those not reporting exposure. No increased risk of PD was found from reported exposure to other occupational hazards, including asbestos, coal or stone dust, chemicals, acids, or solvents.

Previous studies had suggested a link between PD and low-level exposure to pesticides, though the data remains inconclusive. The researchers, led by Alberto Ascherio, associate professor of nutrition and epidemiology at HSPH, looked at data from the Cancer Prevention Study II Nutrition Cohort, a prospective study begun in 1992 by the American Cancer Society. Some 143,325 participants who responded to a follow-up survey in 2001 were included in the HSPH study. Researchers then contacted those individuals in the 2001 survey who reported a diagnosis of PD to ask if their medical records could be reviewed to confirm the diagnosis. Ultimately, Ascherio and his colleagues included in their study a total of 413 cases of PD with onset of symptoms and diagnosis after 1992.

The researchers used exposure data collected in 1982 from the CPS II mortality study, a study from which the Nutrition Cohort was drawn. Exposure to pesticides was reported by 5,203 men (8.2 percent) and 2,661 women (3.3 percent). Among those reporting exposure, after adjusting for age, sex, and other risk factors for Parkinson's disease, there was a 70 percent higher incidence of PD than among people who reported no exposure. Those reporting exposure were more likely to be male than female to report their occupation as farmer, rancher or fisherman and to be blue-collar workers, but none of these factors could account for the increased risk of Parkinson's disease, which was similar in men or women, and in non-farmers as well as farmers. The significant association between pesticide exposure and Parkinson's disease among individuals who are not farmers is most likely explained by use of pesticides at home or in gardening.

Future studies will need to examine which specific pesticides or classes of pesticides are likely to cause Parkinson's disease.

Tuberculosis drug PAS may cure Parkinson's-like illness

Wed, 07 Jun 2006 15:36:37 PST

( from http://www.rxpgnews.com ) Researchers have discovered that a drug used to treat tuberculosis apparently cures patients of a Parkinson's-like illness suffered by thousands of mineworkers, welders and others exposed to high levels of the metal manganese.

Manganese is used to produce steel alloys and as a coating on welding rods, among other industrial applications. It replaced lead decades ago as a component in unleaded gasoline, increasing the risks of manganese intoxication for the general public, said one of the researchers, Wei Zheng, a professor and University Faculty Scholar in Purdue's School of Health Sciences.

When manganese builds up in toxic levels in the body, people suffer from "occupational manganese parkinsonism," which causes symptoms similar to Parkinson's disease. Victims experience hand tremors, poor coordination, unsteady gait and a masklike inability to show facial expressions, Zheng said.

Manganese contained in the coating of welding rods is released in fumes. Welders involved in manufacturing vehicles, tanks and ships are especially prone to manganese intoxication because they work in close quarters, increasing their exposure to the metal, Zheng said.

"There are about 430,000 welders in the United States alone, and even more in China, so manganese intoxication likely affects many people, including workers involved in manganese mining and steel production," he said. "In Beijing, we found a high percentage of welders have these symptoms."

While the condition's symptoms are similar to those of Parkinson's disease, the standard treatments for Parkinson's disease, including the drug levodopa, are not effective for manganese intoxication. A chemical compound called EDTA has been used to help patients eliminate manganese in the urine. The drug's effectiveness, however, is limited because it is water-soluble, preventing it from readily passing through membranes in the "blood-brain barrier," layers of cells surrounding blood vessels that block substances from traveling from the blood into brain tissue.

Ten researchers from institutions around the world including Purdue conducted a 17-year medical follow-up study on a manganese-poisoned worker and about 80 other patients. The researchers learned that an aspirinlike drug called sodium para-aminosalicylic acid, or PAS, dramatically reduces symptoms on a long-term basis.

"The amazing thing is that this drug reverses Parkinson-type symptoms of manganese intoxication," Zheng said. "We see remarkable improvement after treatment with this drug even 17 years later."

PAS has been used for decades to treat tuberculosis and apparently can cross the blood-brain barrier because it is fat-soluble, or lipophilic. That's because the drug contains a structure known as a benzene ring, which enables it to penetrate the membranes.

Findings will appear in the June issue of the Journal of Occupational Environmental Medicine. The paper was written by Yue-Ming Jiang, Xue-An Mo, Feng-Qi Du, Xue Fu and Xia-Yan Zhu, from Guangxi Medical University in China; Hong-Yu Gao and Feng-Ling Liao, from Wuzhou Center for Disease Prevention and Control in China; Jin-Lan Xie from the Wuzhou Worker's Hospital in China; Enrico Pira from the University of Turin in Italy; and Zheng.

The research has focused on China because that country is a major manganese ore producer and provides one-third of the world's supply of steel alloys.

The paper includes data from research involving a female Chinese mineworker who suffered debilitating symptoms, including lack of coordination, trouble walking and writing, and a masklike appearance caused by tense facial muscles. The woman's symptoms nearly disappeared after treatment with PAS in 1987, and she remained free of symptoms when re-examined during a follow-up study in 2004.

The researchers suggest several possible mechanisms that enable the drug to reverse symptoms of the illness. One is that the drug may contain "chelating arms" that grab manganese.

"However, we are not just looking at this drug as a chelating compound, but also as an anti-inflammatory, like aspirin," Zheng said. "Historically, we have believed that neurodegeneration is permanent and cannot be reversed, but PAS appears to shed light on a reversal mechanism.

"It may possibly repair neurons. If this is true, this would be a major finding, but further research will be needed to study this possibility. We think the bigger picture is that the drug might also be used as a treatment for Parkinson's disease, but much more work is needed to confirm this theory."

Stabilizing microtubules with L-AP4 reduces rotenone toxicity

Wed, 19 Apr 2006 20:00:37 PST

( from http://www.rxpgnews.com ) Researchers at the University at Buffalo affiliated with the New York State Center of Excellence in Bioinformatics and Life Sciences have identified a novel agent that can protect neurons involved in Parkinson's disease from being destroyed by the pesticide rotenone.

The agent, called L-AP4, activates a critical group of receptors called group III metabotropic glutamate receptors and may be a promising drug target. Currently there is no known cure for Parkinson's disease.

Long-term studies have shown that environmental toxins play a critical role in the development of Parkinson's disease, and it has been shown recently in research with rats that administering rotenone, a naturally occurring substance widely used as a pesticide, destroys dopamine-producing neurons and causes symptoms of Parkinson's disease in this animal model.

In the April 19 issue of The Journal of Neuroscience, UB researchers lead by Jian Feng, Ph.D., report that activation of group III metabotropic glutamate receptors reverses a cascade of events triggered by rotenone that destroys dopamine neurons.

Feng, UB associate professor of physiology and biophysics, and colleagues earlier demonstrated that microtubules, the intracellular highways for transporting dopamine and many vital cellular components, are critical for the survival of dopamine neurons, which are responsible for controlling body movement.

They showed that rotenone kills dopamine neurons by destroying microtubules, and that stabilizing microtubules greatly reduces the toxicity of rotenone.

In this new study, Feng's group has found that activation of group III metabotropic glutamate receptors by drugs such as L-AP4 triggers a chain of events that leads to microtubule stabilization. This cascade, called the MAP kinase pathway, activates several enzymes that regulate the stability of microtubules.

The primary symptoms of Parkinson's disease are tremors, slowness in movements, and impaired balance and coordination. At least 500,000 people are believed to suffer from Parkinson's disease in the United States, and about 50,000 new cases are reported annually, according to the National Institutes of Health. These figures are expected to increase as the population ages: The average age of onset is about 60. The disorder appears to be slightly more common in men than women.

New Guidelines Improve Diagnosis and Quality of Life for People with Parkinson Disease

Mon, 03 Apr 2006 15:23:37 PST

( from http://www.rxpgnews.com ) New guidelines developed by the American Academy of Neurology aim to educate physicians on the diagnosis and treatment of Parkinson disease and provide people with Parkinson disease an improved quality of life. The guidelines, released at the American Academy of Neurology 58th Annual Meeting in San Diego, Calif., April 1 8, 2006, and published in the journal Neurology, were developed through a rigorous, comprehensive review of all of the scientific evidence available on Parkinson disease.

It is possible to improve the quality of life for people with Parkinson disease, said guideline author and Parkinson expert William J. Weiner, MD, FAAN, of the University of Maryland School of Medicine in Baltimore. The guidelines provide recommendations for: making the correct diagnosis as early as possible, making the best use of time-tested and effective therapies to improve motor function, and screening for and treating depression, psychosis and dementiacommon symptoms of Parkinson disease that often are left untreated.

Parkinson disease is often misdiagnosed. It is estimated that five to 10 percent of people with Parkinson disease are misdiagnosed. Also, up to 20 percent of people diagnosed with Parkinson disease are found to have a different diagnosis during an autopsy. The new guidelines help doctors correctly diagnose Parkinson disease earlier and more accurately. Then neurologists can suggest treatments and lifestyle changes to better manage and treat the disease.

There are a variety of therapies available to treat the motor symptoms of Parkinson disease. The guidelines present how strong the evidence is for each of these drugs and surgery so that physicians can make the best decisions in treating their individual patients. Surprising news includes the wide variety of treatments that are available to help patients with Parkinson disease. No evidence was available to support that nutritional supplements, including vitamin E, are useful in slowing the progress or improving symptoms of Parkinson disease.

Some people have feared that levodopa, one of the most effective treatments for Parkinson disease, may speed up disease symptoms. The guidelines demonstrate that levodopa is a safe and effective treatment to improve movement and does not speed up disease progression. According to a guideline published by the AAN in 2002, either levodopa or a dopamine agonist drug may be used as a first treatment for Parkinson disease.

Movement difficulties can be improved with regular exercise and physical and speech therapy, according to the guidelines. Its important to keep talking with your neurologist about new problems or symptoms or any changes, Weiner said. People often arent aware that exercise and therapy can help with many of these problems.

The guidelines recommend that people with Parkinson disease be screened for and treated for depression, psychosis, and dementia, which can affect quality of life and how well they function. Many people just assume that depression, hallucinations, and memory loss are inevitable side effects of Parkinson disease and dont even discuss them with their neurologist, Weiner said. Effective treatments are available, and treatment can greatly improve the patients quality of life.

Parkinson disease is a progressive movement disorder that affects about one million people in the United States and Canada. In people with Parkinson disease a vital chemical in the brain, dopamine, slowly decreases. Dopamine makes smooth and coordinated muscle movement possible. A loss of dopamine leads to symptoms of Parkinson, such as shaking (tremor), stiffness, shuffling walk, slowness of movements, balance problems, small or cramped handwriting, loss of facial expression, and soft, muffled speech.

Male gene may explain higher incidence of Parkinsons in men

Wed, 22 Feb 2006 01:54:37 PST

( from http://www.rxpgnews.com ) Scientists at Prince Henry's Institute, Melbourne, and the University of California, Los Angeles, have discovered that SRY, the male protein that forms the testes is also produced in the brain region affected in Parkinson's disease. This discovery may explain why men are more likely than women to develop this degenerative disorder.

"Our research has shown that a gene only present in males contributes to the control of physical movement, a fundamental brain function," said Associate Professor Vincent Harley, Head of the Human Molecular Genetics Group at Prince Henry's Institute.

Parkinson's disease is a chronic movement disorder that affects an estimated 40,000 Australians. Men are 1.5 times more likely to develop the disease than women.

SRY, the protein that determines male gender, was discovered by British scientists in 1990. Dr Harley joined the team and was the first to show functions of the SRY protein in males. SRY is passed from father to son on the Y chromosome and is not present in females.

Co-investigators Dr Eric Vilain of UCLA and Dr Harley have now traced the SRY protein to a region of the brain called the substantia nigra, which deteriorates in Parkinson's disease.

Parkinson's disease develops when cells in the substantia nigra begin to malfunction and die, producing less dopamine. Dopamine, a chemical messenger, communicates with the brain to control movement and co-ordination. People with Parkinson's disease become unable to initiate or control their physical movements, eventually leading to paralysis.

The Prince Henry's Institute team, led by Dr Harley, developed sensitive new tools to detect SRY protein in the brain. UCLA scientists, led by Dr Vilain, lowered the level of SRY in the substantia nigra in animal models and detected a corresponding drop in tyrosine hydroxylase, which plays a key role in the brain's production of dopamine. The consequent low dopamine levels resulted in Parkinson's-like movement problems.

Drs Vilain and Harley believe that the variations in genes that control SRY or in the SRY gene itself may be linked to the onset of Parkinson's disease. Men with low levels of SRY may be at greater risk of developing the disease.

"We were surprised to find a function for SRY outside the testes," said Dr Harley.

Scientists at Prince Henry's Institute are collaborating with Associate Professor Catriona McLean, Director of the National Neural Tissue Resource Centre at the Alfred Hospital, Melbourne, to investigate SRY levels in the brains of males with Parkinson's disease.

Drs Harley and Vilain suspect that the normal role of SRY in the male brain could be to provide a protective effect against Parkinson's disease.

"The SRY gene may also explain the sex differences in other dopamine-linked disorders with a higher incidence in males, such as schizophrenia or addiction," said Dr Vilain.

One in seven people with Parkinson's disease are diagnosed before the age of 50 years, and the prevalence increases with age. Parkinson's disease worsens over time, and there is no known cause or cure. The severity and progression of the disease can vary greatly. Symptoms can be managed with medication and surgery.

G2019S mutation is major cause of Parkinson's in Ashkenazi Jewish patients

Thu, 26 Jan 2006 16:41:37 PST

( from http://www.rxpgnews.com ) Researchers at the Albert Einstein College of Medicine of Yeshiva University and its Manhattan hospital affiliate, Beth Israel Medical Center, have found that a specific mutation in a single gene is a major cause of Parkinson's disease among Ashkenazi (Eastern European) Jews. The report will appear in the January 26 issue of The New England Journal of Medicine.

"Like the discovery of the BRCA1 and BRCA2 gene mutations for breast cancer, this finding will directly affect the way Parkinson's disease is diagnosed in Ashkenazi Jews," says Dr. Susan B. Bressman, senior investigator of the report, who also is Chairperson of Neurology at Beth Israel, as well as Professor and Vice Chair of Neurology at Einstein. "It also emphasizes the benefit of focusing genetic studies in a specific ethnic group, even with regard to a disease not thought to be primarily genetic in origin,"

"Up until now, genetic counseling for Parkinson's disease hasn't really been considered," adds study co-author Dr. Laurie J. Ozelius, Associate Professor of Molecular Genetics at Einstein. "Our finding should bring genetic counseling for Parkinson's disease to the forefront along with genetic testing for early detection of Parkinson's disease."

The researchers focused on a gene called LRRK2, which is mutated in about 1% of late-onset non-familial cases of Parkinson's disease in those patients who are primarily of European ancestry.

Their study involved 120 unrelated Ashkenazi Jewish Parkinson's disease patients who had been seen as outpatients at Beth Israel's neurology department and screened for the gene. For comparison, a control group of 317 Ashenazi Jews who did not have Parkinson's disease was also studied. DNA was extracted from white blood cells or cheek cells of all the study participants and analyzed for mutations.

The G2019S mutation--the most common of several possible LRRK2 mutations--was detected in 18.3 percent (22 out of 120) of the Ashkenazi Jewish Parkinson's patients compared with only 1.3 percent (4 out of 317) of control patients.

The mutation's role was even more dramatic when the 120 Parkinson's disease patients were divided into those (37) with a family history of the disease (defined as having at least one affected first, second, or third degree relative) and those (83) with no family history. The G2019S mutation was found in 29.7 percent (11/37) of the familial Parkinson's cases but also in 13.3 percent (11/83) of so-called sporadic or nonfamilial cases. The frequency of this mutation among Ashkenazi Parkinson's patients was 15 to 20 times higher than has been reported among patients of European ancestry in general.

In addition to Ashkenazi Jews, the researchers note that a group of North Africans of Arab descent have been found to have a high frequency of this same gene mutation as a cause of Parkinson's disease. The two groups appear to share the same origin or founder, suggesting a probable Middle Eastern origin for this mutation.

Turning off a mutation linked to Parkinson's disease

Thu, 19 Jan 2006 15:53:37 PST

( from http://www.rxpgnews.com ) A group of Northwestern University researchers is developing a novel gene therapy aimed at selectively turning off one of the genes involved in the development of Parkinson's disease.

The gene therapy, described in the January online issue of the journal Experimental Neurology, was designed by Martha Bohn and her laboratory group at Northwestern University Feinberg School of Medicine.

Bohn is Medical Research Council Professor and director of the neurobiology program at Children's Memorial Research Center and professor of pediatrics and of molecular pharmacology and biological chemistry at the Feinberg School. The gene technique the Bohn lab developed removes a protein known as alpha-synuclein from the diseased dopamine-producing neurons that die in Parkinson's disease. Alpha-synuclein is abundant in structures known as Lewy bodies a diagnostic hallmark of Parkinson's disease.

Research has shown that mutant forms of the alpha-synuclein gene, as well as too much alpha- synuclein protein, are involved in the development Parkinson's disease in some families.

For this research, the Bohn lab combined a recently developed technology called "RNA interference" with gene therapy to turn off alpha-synuclein in dopamine neurons. RNA interference is a sophisticated method to selectively turn off one gene in a cell, leaving others unaffected.

By placing the RNA interference into a crippled, non-disease-causing virus, scientists in the Bohn lab have been able to deliver the RNA interference tool to the brain of rats and turn off the alpha-synuclein protein in neurons. "This is the first step in developing a new therapy for Parkinson's disease based on molecular knowledge of the disease," said Mohan K. Sapru, research assistant professor of pediatrics, who is first author on the study and co-inventor of the gene therapy technology.

"It may also be useful for other diseases of the brain, such as dementia with Lewy bodies, a disease also characterized by Lewy bodies in the brain," Sapru said.

The Bohn lab will subsequently test this gene therapy in mouse models of the disease. If the RNA interference approach works in the mouse, a gene therapy based on silencing the _alpha-synuclein gene will be developed for clinical trials for Parkinson's patients.

Fox Foundation grant funds major gene therapy advance for treatment of Parkinson's disease

Fri, 06 Jan 2006 03:27:37 PST

( from http://www.rxpgnews.com ) An innovative gene therapy approach pioneered by Pennsylvania-based RheoGene Inc. will be further refined and tested in preliminary clinical trials within four years, thanks to a $4.2 million grant from the Michael J. Fox Foundation for Parkinson's Research (MJFF).
A wholly owned affiliate of the University of Pittsburgh Medical Center (UPMC), RheoGene Inc. has developed technology to manage gene expression, a key component of gene-based therapies. RheoGene's therapeutic system uses a patented small-molecule mediator that can turn genes "on" or "off" as well as adjust the level of gene activity similar to the way a rheostat regulates electric current.

"This project has the potential to revolutionize the clinical application of gene therapy not only for the millions of people with Parkinson's disease, but for countless numbers afflicted by other health ailments as well," said Deborah W. Brooks, MJFF president and CEO. "It is a natural fit with the foundation's commitment to drive innovative technology that will have a significant impact on patients' lives."

Parkinson's disease gradually destroys brain cells that produce dopamine, a chemical messenger crucial for the cellular communication that controls muscle movement. As dopamine levels drop, symptoms increase. These include tremors in the arms, legs and face; periodically stiff or frozen limbs; slow movement; and impaired balance and coordination. In the United States, at least 500,000 and perhaps as many as 1.5 million people are thought to have Parkinson's disease, with 50,000 new cases being diagnosed each year, according to the National Institute of Neurological Disorders and Stroke, a division of the National Institutes of Health. Because risk increases with age, these rates will increase as the population ages.

Current treatment options focus on replacing lost dopamine with the drug levodopa (L-dopa), which converts to dopamine in the brain, or brain surgery to control tremors. These treatments generally work temporarily but cannot stop the disease's inevitable progression to disability.

Although research continues on gene-based treatments for a variety of ills, much of the strategy's early promise remains to be realized because of risks associated with failure to regulate gene expression or turn it off entirely if there are worrisome side effects. A RheoGene-led team will work to further the technology, called the RheoSwitch Therapeutic System (RTS), for safe and effective use to control the intensity and timing of gene expression. This will be accomplished using a specially developed Activator Drug that is administered orally to act as an "on switch." When the drug is no longer taken, gene expression stops. Preclinical testing in animal models has indicated that RTS can work as envisioned by researchers.

"We are pleased that the Fox Foundation has recognized that RheoGene's technology has important implications for advancing cell and gene therapies into the clinic," said Thomas Tillett, chief executive officer of RheoGene. "RTS has the potential to provide a critical efficacy and safety mechanism for a wide range of gene-based therapeutics."

The MJFF-funded project will begin with a dual focus. One gene target that researchers will evaluate produces glial cell derived neurotrophic factor (GDNF), a naturally occurring protein that protects and stimulates regeneration of brain cells that secrete dopamine, the same cells that are progressively lost in Parkinson's disease. The other gene target of interest produces aromatic L-amino acid decarboxylase (AADC), an enzyme involved in dopamine synthesis. Both avenues are especially exciting because neurotrophic factors, also known as trophic or growth factors, support critical neuron function and survival.

The team is being led by coordinating principal investigator Dean Cress, Ph.D., a biochemist and co-founder of RheoGene and J. Mark Braughler, Ph.D., head of RheoGene's clinical applications office and laboratory in Pittsburgh. The team includes two experts in gene therapy for Parkinson's disease: Krystof Bankiewicz, M.D., Ph.D., professor of neurological surgery at the University of California, San Francisco and Martha C. Bohn, Ph.D., professor of pediatrics and molecular and biological chemistry at Northwestern University Feinberg School of Medicine, Chicago.

Gene therapy for Parkinson's disease is the first target of the RheoGene-led team's first area of focus. Future research will concentrate on applications to cancers and diabetes.

"RheoGene has been able to reach this stage in its development of RTS and other technologies because of the strategic investment both financial and intellectual made by our partners at UPMC," said Mr. Tillett. "We look forward to continuing to leverage the relationships available to us through our association with the medical center's researchers to deliver hope to many patients using our gene therapy technologies."

Retinal Cell Implants Improve Parkinsonian Motor symptoms

Wed, 14 Dec 2005 17:15:38 PST

( from http://www.rxpgnews.com ) A preliminary study suggests that implants of cells from the human retina improved motor symptoms in patients with Parkinson disease, and they appear to be safe and well tolerated, according to a report in the December issue of the Archives of Neurology, one of the JAMA/Archives journals.

Parkinson disease (PD) is a neurodegenerative disorder characterized by tremor, rigidity, postural instability, and slowed ability to start and continue movements. Most patients with PD require therapy with the medication levodopa to control symptoms three to five years after a diagnosis of PD. However, disease progression and long-term oral treatment with levodopa may lead to the development of motor fluctuations and dyskinesias (difficulty or distortion in performing voluntary movements). Human retinal pigment epithelial (RPE) cells produce levodopa and can be isolated from post mortem human eye tissue, grown in culture, and implanted into the brain attached to microcarriers. These implants have ameliorated the motor deficits in animal models of Parkinson disease, according to background information in the article. (The retinal pigment epithelium is the pigment cell layer found in the inner layer of the retina of the eye.)

Natividad P. Stover, M.D., of the University of Alabama at Birmingham, and colleagues conducted an open-label pilot study to evaluate the effect of unilateral implantation of human RPE cells attached to gelatin microcarriers. Six patients with advanced Parkinson disease received cell implants, which were inserted into the brain tissue. The researchers performed efficacy evaluations at one and three months after surgery, and then at six, nine, 12, 15, 18 and 24 months. Yearly follow-up visits are ongoing and will continue.

"The implants were well tolerated," the authors report. "We observed an average improvement of 48 percent at 12 months after implantation in the Unified Parkinson's Disease Rating Scale motor subscore with the patient in the off state, which was sustained through 24 months."

"Improvement was also observed in activities of daily living, quality of life, and motor fluctuations," they continue. "No off-state dyskinesias were observed."

"On the basis of the motor improvement and tolerability observed in this open-label study, a randomized, double-blind, placebo-controlled study has been initiated to more objectively test efficacy and continue to assess safety," the authors conclude.

LRRK2 (Dardarin) - new drug target for Parkinson's

Sat, 19 Nov 2005 18:20:38 PST

( from http://www.rxpgnews.com ) Researchers at Johns Hopkins' Institute for Cell Engineering (ICE) have discovered a protein that could be the best new target in the fight against Parkinson's disease since the brain-damaging condition was first tied to loss of the brain chemical dopamine.

Over the past year, the gene for this protein, called LRRK2 (pronounced "lark-2"), had emerged as perhaps the most common genetic cause of both familial and unpredictable cases of Parkinson's disease. Until now, however, no one knew for sure what the LRRK2 protein did in brain cells or whether interfering with it would be possible.

Now, after studying the protein in the lab, Johns Hopkins researchers report that the huge LRRK2 protein is part of a class of proteins called kinases and, like other members of the family, helps control other proteins' activities by transferring small groups called phosphates onto them. The researchers also report that two of the known Parkinson's-linked mutations in the LRRK2 gene increase the protein's phosphate-adding activity. The findings appear in the current (Nov. 15) issue of the Proceedings of the National Academy of Sciences.

"We know that small molecules can interfere with this kind of activity, so LRRK2 is an obvious target for drug development," says Ted Dawson, M.D., Ph.D., co-director of the Neural Regeneration and Repair Program within ICE and a leader of the study. "This discovery is going to have a major impact on the field. It's going to get people talking about kinase activity."

Because kinases affect a number of other proteins, LRRK2's link to Parkinson's may be a result of either its own activity or a shift in the activities of one or more "downstream" proteins.

"The next step is to prove that LRRK2 overactivity results in the death of brain cells that produce dopamine, the defining pathology of Parkinson's disease, and to figure out how it does so," says Dawson, who cautions that the large size of the LRRK2 gene and protein could make clinical application of the Hopkins discovery years away.

"For example, we would want to isolate the active part of the LRRK2 protein and use that more manageable part to screen for molecules that would block its activity. But what takes us a second to think of could take four or five months to do," says Dawson. "These things may not come as fast as the field wants."

The LRRK2 protein, sometimes called dardarin, is 2,527 building blocks long. In contrast, the alpha-synuclein protein, the first to be linked to Parkinson's disease, is only 140 building blocks long. The parkin protein, linked to more cases of familial Parkinson's disease than any other to date (although LRRK2 is likely to break that record), is considered "big" at 465 building blocks long.

Undaunted by the size of the LRRK2 gene and protein, Andrew West, Ph.D., a postdoctoral fellow and co-first author of the paper, spent months extracting the full-length gene from human brain samples and developing reliable experiments to test how mutations affected LRRK2's activity. Co-first author Darren Moore, Ph.D., also a postdoctoral fellow, built the tools to get bacteria to make mounds of LRRK2 protein and two mutant versions and also tracked down the LRRK2 protein's location inside cells.

The research team's experiments showed that the LRRK2 protein, in addition to its role as a kinase, actually sits on mitochondria, cells' energy-producing factories, where it likely interacts with a complex of proteins whose failure has also been implicated in Parkinson's disease.

Mutations in LRRK2 were first tied to Parkinson's disease in 2004 and to date explain perhaps 5 percent to 6 percent of familial Parkinson's disease (specifically so-called autosomal dominant cases, in which inheriting a single faulty copy of the gene results in disease) and roughly 1 percent of Parkinson's disease in which there is no family history. But few of the gene's genetic regions have been analyzed in depth.

"As researchers comb through the rest of the LRRK2 gene, it seems likely that more mutations will be found and that it will be tied to more varieties of the disease," says Dawson. What's known about LRRK2 so far suggests that it might connect diseases long thought to be distinct, particularly Parkinson's disease and conditions known as "diffuse Lewy body disease," named for the bundles of certain proteins that build up inside cells in the brain in affected people. As a result, studying LRRK2 might improve understanding of and eventually treatment for more than just Parkinson's disease itself, Dawson says.

First whole genome map of genetic variability in Parkinson's disease

Wed, 14 Sep 2005 02:36:38 PST

( from http://www.rxpgnews.com ) Mayo Clinic researchers in collaboration with scientists at Perlegen Sciences, Inc. and funded by the Michael J. Fox Foundation for Parkinson's Research have produced the first large-scale whole genome map of genetic variability associated with Parkinson's disease. Their results highlight changes in 12 genes that may increase the risk for Parkinson's disease in some people. Parkinson's disease is a disabling and currently incurable disease that affects millions of people worldwide.

Mayo Clinic and Perlegen Sciences will report their findings in The American Journal of Human Genetics. The paper was published online Friday, Sept. 9 (www.ajhg.org) and will appear in the November 2005 print issue.

"This represents one of the first large-scale whole genome association studies of any disease," said the study's first author, Mayo Clinic neurologist Demetrius Maraganore, M.D. "It is something we've wanted to do for years, and now we finally had the technology and funding to make it happen. If confirmed, the findings may lead to new insights about the causes of Parkinson's disease."

Significance of the Findings

Both the findings and the technology that produced them are groundbreaking, representing one of the most comprehensive genetic studies of Parkinson's disease to date with nearly 200 million genetic tests (genotypes) completed. To accomplish this, researchers initially studied the association of about 200,000 single-letter variations in the genome known as single nucleotide polymorphisms, or "SNPs" (pronounced "snips") in patients with Parkinson's disease. The study examined DNA from 775 people with Parkinson's disease (cases) and from 775 people without Parkinson's disease (controls).

"To be most effective, a whole genome association study requires accurate testing of a large number of SNP markers that are distributed across the human genome in a dense and informative pattern," says Dr. Maraganore. "In this respect, our collaborators at Perlegen have set a new standard."

"In one year, the Michael J. Fox Foundation and Mayo Clinic have generated results that will greatly focus future research efforts in Parkinson's disease," explained David Cox, M.D., Ph.D., chief scientific officer of Perlegen Sciences. "If replication of only one of these findings leads to a better understanding of the causes of the disease or improvements in the early detection or treatment of patients, we will have made significant progress."

Noteworthy findings include:

* Confirmation that variation in two previously known regions of the genome, PARK10 and PARK11, are likely associated with Parkinson's disease susceptibility.

* Identification of 10 additional SNPs that appear to be associated with Parkinson's disease susceptibility. Some of these are in or near genes with direct biological relevance to the disease. For instance, one of these, the SEMA5A gene, may play an important role in both the development and programmed death of dopamine-producing nerve cells in the brain. Selective degeneration of dopamine neurons in the brain is a hallmark feature of Parkinson's disease.

Susceptibility genes are genes that may make some people more or less likely to develop a disease but that do not necessarily cause the disease directly. The authors note that in this study, the size of the effect was small for any single SNP; combinations of gene variants or interactions with environmental factors may be necessary to develop Parkinson's disease.

"This study represents the first large-scale attempt to assess the contribution of genes to susceptibility and development of Parkinson's disease," said Kenneth Olden, Ph.D., Sc.D., chief scientific advisor for the Michael J. Fox Foundation and former director of the National Institute of Environmental Health Sciences (NIEHS) of the National Institutes of Health. "If confirmed, the finding of 12 potential susceptibility genes is significant. However, equally significant is the fact that this comprehensive study found no strong single genetic determinant of Parkinson's disease." The Michael J. Fox Foundation is organizing a large-scale validation study of the initial findings.

MAO-B inhibitors do not appear to slow Parkinsons disease progression

Thu, 25 Aug 2005 06:03:38 PST

( from http://www.rxpgnews.com ) FA class of drugs known as MAO-B inhibitors may be effective in improving motor symptoms in people with early Parkinsons disease and may delay the need for treatment with other drugs, according to a new systematic review of current evidence.

However, contrary to results from other studies, the researchers found that MAO-B (monoamine oxidase B) inhibitors do not appear to slow the diseases progression.

The benefits of MAO-B inhibitors are small but may be worthwhile in some patients, says Carl Counsell of the University of Aberdeen in Scotland and an author of the review. I dont think our review supports a policy of putting all newly diagnosed patients on an MAO-B inhibitor, but some patients may wish to try it.
The review appears in the current issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.

Parkinsons disease is a motor system disorder that results from the loss of dopamine-producing brain cells. There is no blood or laboratory test to diagnose Parkinsons and no cure. Current treatment involves the use of drug therapies such as levodopa (L-dopa), which nerve cells use to make dopamine and replenish the brain's dwindling supply, thus improving symptoms.

However, L-dopa becomes less effective over time, and the response to the drug can become erratic, causing fluctuations in motor symptoms and fragmented, jerky motions. Drugs such as MAO-B inhibitors have been under study to delay disease progression and postpone the use of L-dopa.

We did not find any convincing evidence that MAO-B inhibitors significantly delay disease progression in early [Parkinsons], the authors write. Although there is good evidence that MAO-B inhibitors have a levodopa-sparing effect, whether this results in fewer long-term, clinically relevant motor complications is unclear.
At present we do not feel these drugs can be recommended for routine use in the treatment of early Parkinsons disease, the authors conclude, "but further randomized controlled trials should be carried out to clarify, in particular, their effect on deaths and motor complications.

In the review, researchers looked at 10 clinical trials and 2,422 patients with early Parkinsons who had either not received treatment or had started treatment within the last 12 months. There were three groups of patients followed for an average of almost six years: those given an MAO-B inhibitor (selegiline or lazabemide), those given no treatment and those given a placebo.

The patients on MAO-B inhibitors did have reduced impairment and disability over the short term and few side effects, except one trial that showed increased mortality in patients taking the drugs.

The existing data do not exclude the possibility that MAO-B inhibitors cause an increase in mortality but, given that only one trial has suggested this, we consider it very unlikely, the authors write.

MAO-B inhibitors delay the need for levodopa by about six months in patients with early disease, says Counsell. However, this is almost certainly because they have a mild symptomatic effect rather than fundamentally altering the progression of the disease. The question is whether this short delay is important.

I suspect that selegiline delays motor fluctuations as it continuously delivers dopamine, says Irene Litvan, M.D. of the University of Louisville School of Medicine. The unresolved question is if it is truly worthwhile prescribing MAO-B inhibitors. Perhaps rasagiline, another MAO-B inhibitor which is more potent, may have more of a future in treating [Parkinsons] as is offers additional benefits, for instance, as an antioxidant.
Rasagiline is newly licensed MAO-B inhibitor. I would favor selegiline for further study because this is the most widely used; many would favor rasagiline because newer is often perceived as better, Counsell says.

The main symptoms of Parkinsons are subtle and gradually worsen, and include trembling in hands, arms, legs, jaw and face; rigidity, or stiffness of the limbs and trunk; slowness of movement; and postural instability, impaired balance and coordination. As the disease progresses, patients may have difficulty walking, talking or completing other simple tasks. Depression and other emotional changes can also occur.

How rotenone destroys the dopamine neurons

Thu, 25 Aug 2005 05:19:38 PST

( from http://www.rxpgnews.com ) Neuroscientists from the University at Buffalo have described for the first time how rotenone, an environmental toxin linked specifically to Parkinson's disease, selectively destroys the neurons that produce dopamine, the neurotransmitter critical to body movement and muscle control.

Microtubules, intracellular highways that transport dopamine to the brain area that controls body movement, are the crucial target, they report.

Damage to microtubules prevents dopamine from reaching the brain's movement center, causing a back-up of the neurotransmitter in the transport system, the researchers found. The backed-up dopamine accumulates in the body of the neuron and breaks down, causing a release of toxic free radicals, which destroy the neuron.

The study appeared in the Aug. 9 issue of the Journal of Biological Chemistry.

"This study shows how an environmental toxin affects the survival of dopamine neurons by targeting microtubules that are critical for the survival of dopamine-producing neurons," said Jian Feng, Ph.D., assistant professor of physiology and biophysics in the UB School of Medicine and Biomedical Sciences and senior author on the study.

"Based on these findings, we have identified several ways to stabilize microtubules against the onslaught of rotenone. These results ultimately may lead to novel therapies for Parkinson's disease."

At least 500,000 people are believed to suffer from Parkinson's disease in the United States, and about 50,000 new cases are reported annually, according to the National Institutes of Health. These figures are expected to increase as the population ages: The average age of onset is about 60. The disorder appears to be slightly more common in men than women.

Feng and colleagues in the Department of Physiology and Biophysics have concentrated their research on the cellular mechanisms of the disease. They are interested specifically in understanding why rotenone destroys neurons that produce dopamine, while sparing neurons that produce other neurotransmitters.

Using cultures of rat neurons, the researches subjected neurons that produce various types of neurotransmitters to agents that mimic the action of rotenone. These results showed that dopaminergic neurons were destroyed while others survived.

They then topped off the treatment by adding the drug taxol, which stabilizes microtubules and prevents their breakdown. Findings showed that by protecting microtubules, the toxic effect of rotenone on dopamine-producing neurons was greatly reduced.

"Based on these findings, we believe that microtubules are a critical target of PD environmental toxins such as rotenone," said Feng. "Since many microtubule-depolymerizing agents are compounds naturally produced in many plants, our research points to the need to examine their possible link to Parkinson's disease. In addition, PD has a higher incidence in rural areas and is associated with pesticides and insecticides frequently used in farming practices."

The research also opens up novel avenues for the development of PD therapies by targeting microtubules, he said. Feng and colleagues in his laboratory are working actively towards this goal.

Loss of nerve fibres reversed in Parkinsons for first time

Mon, 04 Jul 2005 00:26:38 PST

( from http://www.rxpgnews.com ) Analysis of the brain of a patient suffering from Parkinson's Disease has shown that the experimental treatment he received caused regrowth of the nerve fibres that are lost in this disease. The findings are reported in the July issue of Nature Medicine.

This is the first time that any treatment has been shown to reverse the loss of nerve fibres in Parkinson's Disease.

The 62-year-old man was one of five patients in a pilot study carried out by Mr Steven Gill at Frenchay Hospital in Bristol, UK. In this study, an experimental drug (GDNF) was pumped through a fine catheter into a damaged part of the brain. Within a couple of months, patients were noticing dramatic improvements in their ability to move, and these continued over almost four years of treatment. Even after ceasing medication, the patients' improvement has been maintained.

After the death of the 62-year-old patient from a heart attack, Professor Seth Love from Bristol University was able to examine his brain. Because the GDNF had been infused into one side of the brain only, the effects of the treatment could be assessed by comparing the two sides.

In Parkinson's Disease, nerves containing the chemical messenger dopamine are lost from a region of the brain region known as the putamen, leading to tremors and other motor abnormalities characteristic of the disease.

Professor Love found that dopamine-containing nerve fibres had sprouted back in the putamen. He said: "This is the first neuropathological evidence that infusion of GDNF in humans causes sprouting of dopamine fibres, in association with a reduction in the severity of Parkinson's Disease." The findings may revitalise interest in GDNF administration as a potential therapy for this degenerative condition, providing renewed hope for patients disappointed by the recent withdrawal of this drug due to concerns about its safety.

GDNF, which stands for glial cell line-derived neurotrophic factor, is a natural growth agent needed by brain cells to produce dopamine, which transmits impulses between certain nerve cells including those that regulate movement. A reduced concentration of dopamine in the brain is associated with Parkinson's Disease.

Protein formation insights in Parkinson's disease

Wed, 22 Jun 2005 12:55:38 PST

( from http://www.rxpgnews.com ) Researchers at UT Southwestern Medical Center have discovered a mechanism that causes a protein to clump together in brain cells of people with Parkinson's disease, pointing toward a possible treatment for the condition.

The protein clumping is part of a "vicious cycle," the researchers said. As the proteins cluster, they inhibit an enzyme that normally breaks them down, leading to the formation of even more masses.

"It's a disease involving accumulation of a protein in an aberrant form," said Dr. Philip Thomas, professor of physiology at UT Southwestern and senior author of the study. The research, available online, was published in the June 17 issue of The Journal of Biological Chemistry.

The findings have parallels to other diseases in which protein clusters form in and around nerves, such as Huntington's and Alzheimer's disease.

The culprit in Parkinson's is the protein alpha-synuclein, which normally appears in a long, folded form in cells. It's known to be linked to the disease because mutations in it cause rare, inherited cases of early-onset Parkinson's.

Normally, if a cell becomes stressed, alpha-synuclein unfolds, and an enzyme degrades it completely into harmless bits to prevent the clumping. In Parkinson's patients, however, some of the degrading enzyme malfunctions and creates truncated fragments of alpha-synuclein rather than the harmless bits.

UT Southwestern researchers found
that these truncated fragments act like "seeds," encouraging the unfolded form of alpha-synuclein to gather around them. It doesn't take much - just a few molecules of the truncated fragments - to activate this process. Eventually, the cluster is big enough to form a structure called a fibril.

The two forms of the enzyme are usually in balance, with the normal activity outperforming the malicious activity, Dr. Thomas said.

But when the system goes out of balance, the fibrils suppress the normally functioning enzyme, preventing it from fully breaking down the unfolded alpha-synuclein, resulting in even more of the protein being available to form clumps. The clumps also alter the structure of the enzyme in such a way that it produces even more seed fragments. This leads to the formation of more clumps, and so on.

Scientists are still debating which form of the alpha-synuclein protein actually damages the cells, said Dr. Chang-Wei Liu, research fellow in physiology at UT Southwestern and lead author of the study. It could be the mature fibril, or one of the intermediate forms that appears during the degradation process, he said.

Future research may involve uncovering methods to inhibit just the malicious form of the enzyme, while leaving the functions of the normal enzyme unaffected, Dr. Thomas said. Inhibiting only one form is vital, because the normal enzyme is necessary for cells to survive.

Still, the finding reported in The Journal of Biological Chemistry "gives us clues about potential new treatment avenues," he said.

Phase I trial of Gene Therapy to Treat Parkinson's Disease Nears Completion

Sun, 24 Apr 2005 16:33:38 PST

( from http://www.rxpgnews.com ) Neurologix Inc. (OTCBB:NRGX) today announced that on April 20, 2005, its scientific co-founder, Michael G. Kaplitt, M.D. Ph.D., presented a clinical update as the Company sponsored landmark Phase I gene therapy trial for the treatment of Parkinson's disease nears completion. This update was given at the 73rd annual meeting of the American Association of Neurological Surgeons (AANS) held in New Orleans.

Dr. Kaplitt highlighted the rationale for targeting the overactive subthalamic nucleus in Parkinson's disease patients with the GAD (glutamic acid decarboxylase) gene, which synthesizes the major inhibitory neurotransmitter in the brain, gamma-aminobutyric acid (GABA).

He also reported that he completed the surgical gene therapy procedure on a total of 11 patients at The New York Presbyterian Hospital/Weill Medical College of Cornell University. These patients are being monitored and evaluated neurologically before and for one year after surgery by Drs. David Eidelberg and Andrew Feigin at the North Shore Hospital Long Island Jewish Movement Disorder Clinic. The first four patients were treated with the lowest-dose and have now been followed for more than one year. Three of the four patients treated in the second, mid-dose cohort have been followed for more than six months. The remaining four patients, including three in the highest dose cohort, have been followed for intervals up to six months.

The primary outcome measure of this phase I study is safety, and Dr. Kaplitt reported that to date there has been no evidence of any treatment-related adverse effects.

About the Neurologix Phase I Clinical Trial

The Phase I trial, which is the first FDA-approved clinical trial to test gene therapy to treat Parkinson's disease, is an open-label dose-escalation study with four patients in each of three escalating dose cohorts. The third cohort of four patients receives 10 times the dose of the first cohort. The 12 patients participating in the trial must have been diagnosed with severe Parkinson's disease of at least five years duration and who no longer adequately respond to current medical therapies.

The Gene Therapy Procedure

The surgery entails a stereotactic neurosurgical procedure performed under local anesthesia. First, MRI is used to image the target subthalamic nucleus (STN) region of the brain.

The STN is mapped using microelectrodes by recording from single neurons as the electrode is slowly moved towards the STN. Once a signature firing pattern is obtained confirming that the electrode is in the STN, the fine-wire electrode is removed, leaving only the microelectrode sheath through which a hair-thin (170 microns) hollow tube is inserted.

Thirty-five microliters containing 3.5 billion particles of the "AAV" (adeno associated virus) viral vector (and a correspondingly higher dose in subsequent cohorts) containing a GAD gene (cDNA), is then infused at 0.5 microliters/minute, together with 15 microliters of 25% mannitol. After the 100-minute infusion period, the delivery catheter is withdrawn and the incision is closed. No hardware is left behind following this procedure.

"We are pleased and encouraged with our progress to date and look forward to the next phase, which will focus on the efficacy of our proprietary treatment for patients with this disease," said Dr. Michael Sorell, CEO of Neurologix.

A self-management rehabilitation study for Parkinsons disease

Thu, 14 Apr 2005 16:06:38 PST

( from http://www.rxpgnews.com ) A self-management rehabilitation study at Boston University (BU) Sargent College of Health and Rehabilitation Sciences may help people with Parkinsons disease restore function and improve quality of life.

Investigators at Boston University and Boston Medical Center received a three year, one million dollar grant from the National Institute of Health and National Institute on Aging to study the effectiveness of a self-management multidisciplinary rehabilitation program for people with Parkinsons disease. The goal of the study is to determine whether a specialized rehabilitation program, led by licensed physical, occupational and speech therapists, can help people with Parkinsons disease improve their ability to function in day-to day life.

Participants in the program attend therapy sessions at Sargent College, BU for six weeks where they learn strategies to improve functional abilities such as handwriting, walking, speaking louder and getting up from the floor. In addition, participants are instructed in specific strengthening and stretching exercises to improve overall mobility. Through discussions with therapists and other participants, individuals with Parkinsons disease learn the skills necessary to manage the disease more effectively over the long-term.

Participants such as Christie Mostone, of Medford, MA, have shown much improvement with walking, flexibility, and performing daily tasks after this six week program. Those with the greatest, long term improvement were those who continued practices they learned during the program on their own after it was over.

When asked about his experience with this program, Mostone said, For me, it was the first sign of hope. I was afraid to do things before, and now Im not. Im even able to go fishing with my grandson.

Mostone estimates that his quality of life has improved about 30% since beginning this program.

Combining these three therapies helps participants learn to manage their symptoms even in the earliest stages of the disease, said Robert Wagenaar, PhD, principle investigator of the study and chairman of the department of rehabilitation sciences at BU Sargent College. Previous research shows that rehabilitation can improve the functional capabilities of people with Parkinsons disease. We aim to provide participants with the tools they need to improve their day-to-day function.

New Parkinson's Disease Gene Mutation is Very Common in North Africa

Wed, 13 Apr 2005 00:20:38 PST

( from http://www.rxpgnews.com ) The newest gene for Parkinson's disease, LRRK2, is proving to be a very common cause of familial PD. Recent studies have shown it is responsible for up to 6 percent of familial cases in North America and Europe.

In this study, researchers found that 41 percent of autosomal dominant PD in North African patients were due to a single mutation in the gene, which is also the most common mutation in other populations.

As has been seen in other populations, younger mutation carriers were less likely to be affected, indicating the existence of age-dependant penetrance for the gene mutation.

Physical exercise linked to lower risk of Parkinsons

Tue, 22 Feb 2005 18:12:38 PST

( from http://www.rxpgnews.com ) In the first comprehensive examination of strenuous physical activity and the risk of developing Parkinson's disease, researchers from the Harvard School of Public Health (HSPH) have found that men who exercised regularly and vigorously early in their adult life had a lower risk for developing Parkinson's disease compared to men who did not. The findings appear in the February 22, 2005 issue of the journal Neurology.
Parkinson's disease is a progressive nervous disease occurring generally after age 50. It destroys brain cells that produce dopamine and is characterized by muscular tremor, slowing of movement, rigidity and postural instability.

Men who were the most physically active at the start of the study cut their risk of developing Parkinson's disease by 50 percent compared to men study participants who were the least physically active. The authors also found that men who reported regularly having engaged in strenuous physical activity in early adult life cut the risk for Parkinson's by 60 percent compared to those who did not.

Among women in the study, strenuous activity in the early adult years was also linked to a lower risk of Parkinson's, but this relationship was not statistically significant, and there was no clear relationship between physical activity later in life and Parkinson's risk.

To examine the relationship between physical activity and Parkinson's disease, participants were chosen from the Health Professionals Follow-Up Study at HSPH and the Nurses' Health Study, a Brigham and Women's Hospital-based study. More than 48,000 men and 77,000 women, who were free of Parkinson's disease, cancer or stroke, were included. Participants completed comprehensive questionnaires on disease, lifestyle practices and physical and leisure time activities beginning in 1986 and were updated every two years through 2000. During the course of the study, 387 cases of Parkinson's disease (252 men and 135 women) were diagnosed among the study participants.

The questionnaires contained inquiries on activities such as walking, hiking, jogging, running, bicycling, lap swimming, tennis, squash, racquetball, aerobic exercising and other activities. Additionally, participants were asked to report the number of flights of stairs they climbed per day ranging from two to 15.

Alberto Ascherio, senior author and associate professor of nutrition and epidemiology at the Harvard School of Public Health, said: "These are intriguing and promising findings that suggest that physical activity may contribute to the prevention of Parkinson's. A protective effect of physical activity has been recently found in an animal model of Parkinson's disease -- this convergence of epidemiological and experimental data is what we are looking for, because consistent results are more likely to reflect biological mechanisms with important clinical implications. Future studies should also address the possibility that physical activity slows the progression of Parkinson's."

Most common genetic cause of Parkinson's disease identified

Wed, 16 Feb 2005 19:28:38 PST

( from http://www.rxpgnews.com ) Two new studies strongly suggest that a mutation in a recently discovered gene is the most common genetic cause of Parkinson's disease identified to date. The discovery by an international research team provides fresh evidence that genetics may contribute to the development of some cases of Parkinson's disease. The findings could lead to the development of a genetic test to detect the mutation in individuals at risk. The research team includes investigators at the National Institute on Aging (NIA) and scientists supported by the National Institute of Neurological Disorders and Stroke (NINDS).

Parkinson's disease, which affects at least 500,000 Americans, is a progressive neurologic disorder that is caused by the degeneration of nerve cells in the portion of the brain that controls movement. Scientists have long suspected genetics plays a role in the onset of the disease. In these studies, the investigators found that a mutation in the gene LRRK2 appears to occur in at least one of every 60 people who have the disease. Overall, the mutation could be responsible for up to 5 percent of Parkinson's disease in people with a family history of the disorder and may account for 1½ to 2 percent of cases in individuals who do not have a family history of the disease. The researchers found a mutation in one copy of the gene can lead to the disease. The findings were published online by Lancet at 6:30 p.m. ET on January 17, 2004.

"Among the forms of Parkinson's disease that are genetic in origin, this gene mutation causes more cases of Parkinson's disease than any other gene discovered to date," says Andrew Singleton, Ph.D., chief of the Molecular Genetics Unit in the NIA's Laboratory of Neurogenetics. "Knowing that this mutation is not only important in familial forms of disease, but in typical sporadic disease, where there is no strong family history, could lead to earlier detection of Parkinson's disease. Further study of how this gene works also might help scientists identify new treatments."

In addition to Dr. Singleton, the collaborative work was spearheaded by William C. Nichols, Ph.D., of Cincinnati Children's Hospital, Tatiana Foroud, Ph.D., of Indiana University Medical Center, Indianapolis, and Nicholas W. Wood, M.D., of the Institute of Neurology in London. The NIA and the NINDS are part of the National Institutes of Health (NIH) at the U.S. Department of Health and Human Services.

Singleton and his colleagues recently discovered LRRK2, a gene that encodes a protein named dardarin by the researchers from the Basque word dardara, which means tremor, a major symptom of Parkinson's disease. It was isolated on a region of chromosome 12 called PARK8 by investigators who studied five families with a history of Parkinson's disease who lived in the Basque region of Spain and in England.

In these new studies, the researchers sought to determine the prevalence of the genetic mutation in other families and individuals being studied by the Parkinson's Study Group with NINDS support. In an analysis of 358 families with a history of Parkinson's disease, for instance, the investigators found that 34 of the 767 people who had inherited the disease had at least one copy of the mutated gene. Similarly, the team detected one copy of the mutation in 8 of 482 people with Parkinson's disease, but who didn't report a family history of the disease. The Parkinson's Study Group is a non-profit, cooperative group of Parkinson's disease experts from 59 medical centers in the United States and Canada who are dedicated to improving treatment for people affected by Parkinson's disease.

"NINDS is pleased to have supported the collection of this large group of families and sibling pairs, which is proving to be an invaluable resource for these studies," says Diane Murphy, Ph.D., a program director at NINDS. "Because the prevalence of this mutation is 5 percent in families with a history of the disease and it is relatively common even among those without a family history, it's possible that detecting this mutation will help identify people at increased risk for Parkinson's disease."

About 50,000 Americans are diagnosed with Parkinson's disease each year. The disease occurs when certain nerve cells die or become impaired and can no longer produce dopamine, a brain signaling chemical (neurotransmitter). Without it, individuals can develop tremor or trembling in hands, arms, legs, jaw, and face; rigidity or stiffness of the limbs and trunk; bradykinesia, or slowness of movement; and postural instability or impaired balance and coordination. Patients may also have difficulty walking, talking, or completing other simple tasks. The disease is both chronic and progressive. Incidence of the disease increases with age, with an average onset at about 60 years.

Rasagiline Significantly Reduces 'OFF' Time in Parkinson's - Study shows

Tue, 15 Feb 2005 08:14:38 PST

( from http://www.rxpgnews.com )

Patients with moderate-to-advanced Parkinson's disease (PD) experiencing motor complications who added once-daily AGILECT(R) (rasagiline tablets) to their treatment with optimized levodopa with or without stable doses of other anti-PD medications experienced a significant improvement in their PD symptoms and a significant reduction in "off" time according to the "PRESTO" study published in the February issue of Archives of Neurology.Rasagiline was dosed once-daily and required no titration.

"Results from this study show benefits of rasagiline compared with placebo in moderate-to-advanced levodopa-treated PD patients experiencing motor complications. During disease progression and after months or years of levodopa therapy, these patients commonly experience motor complications, such as unpredictable fluctuations between 'on' and 'off' time," said Ira Shoulson,M.D., professor of neurology at the University of Rochester School of Medicine and principal investigator of the Parkinson Study Group (PSG),the organization that conducted the "PRESTO" trial. "This study showed that rasagiline demonstrated significant benefit in reducing 'off' time, increasing 'on' time, and improving features of Parkinson's disease."

The multicenter, randomized, placebo-controlled, double-blind, parallel
group "Parkinson's Rasagiline: Efficacy and Safety in the Treatment of 'Off'" (PRESTO) study included 472 PD patients who were experiencing at least 2.5 hours of daily "off" time despite optimized treatment with levodopa with or without stable doses of other anti-PD medications at 57 PSG sites in the United States and Canada.

Many patients enrolled were treated, in addition to levodopa, with
dopamine agonists, entacapone and/or anticholinergic medications. Patients received 1 mg or 0.5 mg Rasagiline tablets or placebo once daily.The average reduction in "off" time among patients using Rasagiline was 1.85 hours daily for the 1 mg group and 1.41 hours daily in the 0.5 mg group,while placebo provided a reduction of 0.91 hours daily.

Additionally, rasagiline significantly improved motor function during "on"time (time when medication effectively manages symptoms of PD) and activities of daily living during "off" state based on the Unified Parkinson's Disease Rating Scale (UPDRS). The UPDRS is a research tool commonly used to measure a PD patient's ability to perform motor and mental tasks and activities of daily life.Rasagiline also showed significant improvement on Clinical Global Improvement (CGI) scale scores rated by the examiner. Quality of life,as measured by the PD -- Quality of Life (PDQUALIF) scale, showed a trend toward improvement in patients treated with rasagiline 0.5 mg/day, but not with rasagiline 1 mg/day.

"Rasagiline decreased 'off' time and increased the amount of 'on' time,"
said Matt Stern, M.D., professor of neurology at the University of
Pennsylvania and co-principal investigator for the PRESTO study. "The efficacy and tolerability of rasagiline, as demonstrated in this trial, combined with its once-daily dosing, suggest it may be a promising new treatment for PD."

Patients on rasagiline experienced side effects similar to those of
patients on placebo.Adverse events significantly more common with rasagiline than with placebo were balance difficulty in the 0.5 mg rasagiline group, and weight loss, vomiting, and anorexia in the 1 mg rasagiline group.

Balance difficulty occurred slightly more often in the rasagiline treated patients, but did not appear to be dose-related.Dyskinesias were reported as an adverse event in 10 percent of patients receiving placebo and 18 percent of patients receiving either dosage of rasagiline but did not lead to early terminations.

Rasagiline is a novel, potent, second-generation, selective, irreversible
monoamine oxidase type-B (MAO-B) inhibitor that blocks the breakdown of dopamine, a substance in the brain needed to facilitate movement. A new drug application for rasagiline for the treatment of PD was submitted to the U.S.Food and Drug Administration (FDA) Sept. 5, 2003. Indications are being sought for once-daily rasagiline as a monotherapy in early PD and as an adjunct to levodopa in moderate-to-advanced disease.

Parkinson's disease is a degenerative disorder of the brain. Symptoms can include tremor, stiffness, slowness of movement and impaired balance. An estimated one million North Americans have PD, which usually affects people over the age of 50.

Teva Neuroscience, Inc. and Eisai Inc. will co-promote rasagiline in the United States, once approved by the FDA, as part of a long-term strategic alliance between Teva Pharmaceutical Industries Ltd. and Eisai Co., Ltd. Teva and H. Lundbeck A/S will co-promote the product in Europe, upon expected receipt of Marketing Authorization in Q1 2005.

PCBs, fungicide make brain cells vulnerable for Parkinson's

Thu, 10 Feb 2005 17:47:38 PST

( from http://www.rxpgnews.com ) University of Rochester scientists investigating the link between PCBs, pesticides and Parkinson's disease demonstrated new and intricate reactions that occur in certain brain cells, making them more vulnerable to injury after exposures.

In two papers published in the journal NeuroToxicology (Dec. 2004 and Feb. 2005), the group describes how polychlorinated biphenyls (PCBs) disrupt dopamine neurons, which are the cells that degenerate during the course of Parkinson's disease. Researchers also show that low levels of maneb, a fungicide commonly used in farming, can injure the antioxidant system in those same types of cells. Environmental contaminants might make dopamine cells more vulnerable to damage from normal aging, infection, or subsequent exposure to pollutants, researchers say.

The investigation is part of a nationwide race to better understand every aspect of Parkinson's disease, which affects up to 1 million Americans. It is a progressive neurological disorder that occurs when certain nerve cells in the substantia nigra region of the brain die or can no longer produce the brain chemical dopamine. A lack of dopamine is what causes patients to experience tremors, stiffness in the limbs and trunk, and impaired movement or balance.

In the 1990s scientists reported that the brains of Parkinson's patients contained elevated levels of PCBs and certain pesticides. While researchers believe that genetics, the aging process and exposure to toxicants all play a role in the development of Parkinson's, the group led by Lisa Opanashuk, Ph.D., is focused on environmental exposures. The National Institute of Environmental Health Sciences is funding the work.

"If we can identify the mechanisms by which PCBs or pesticides perturb dopamine neuron function, it may lead to the development of therapies that can prevent, slow or stop the progression of Parkinson's," says Opanashuk, an assistant professor of Environmental Medicine.

PCBs create havoc in the body's cellular system by producing free radicals, which leads to a process known as oxidative stress (OS). Oxidative stress is thought to be one of the main causes of cell degeneration. Normally, antioxidants can balance the damage done by OS. But toxic pesticide exposure, combined with the normal aging process, shifts the equilibrium toward oxidative stress and neurodegeneration.

The Rochester studies demonstrate, for the first time, the intricate OS and antioxidant responses to PCBs in dopamine neurons. Investigators treated dopamine cells and other brain cells with PCBs and documented the activation of oxidative-stress related pathways. Further research will evaluate how PCBs become risk factors for disease.

PCBs, used as industrial coolants and lubricants, were banned in 1977 but remain widespread in the environment due to their improper disposal. They linger in the food chain, particularly in wild and farmed salmon and other fish. PCBs accumulate in the body in fat and brain cells and other tissues. The potential adverse health effects of PCBs are dependent upon many factors, such as the levels of exposure, the toxicities of individual chemicals present in any given mixture, and their interactive properties.

Pesticides such as maneb remain in farmed soil for 20-75 days following application and can be found on produce for more than three weeks, even after washing, according to researchers. Until now, the effect of maneb on oxidative stress responses in dopamine neurons was unknown.

But Opanashuk's group shows that just as in exposure to PCBs, cells treated with low levels of maneb also undergo changes that disturb the balance in the antioxidant defense system. Another concern is whether maneb causes more damage when people are exposed in combination with other pesticides, which occurs in rural communities. Opanashuk hopes the research will lead to developing safety guidelines and determining more closely the role that maneb plays in neurological diseases.

Transplantation of monkey embryonic stem cells reverses Parkinson disease in primates

Tue, 04 Jan 2005 19:27:38 PST

( from http://www.rxpgnews.com ) The replenishment of missing neurons in the brain as a treatment for Parkinson disease reached the stage of human trials over 15 years ago, however the field is still in its infancy. Researchers from Kyoto University have now shown that dopamine-producing neurons (DA neurons) generated from monkey embryonic stem cells and transplanted into areas of the brain where these neurons have degenerated in a monkey model of Parkinson disease, can reverse parkinsonism. Their results appear in the January 3 issue of the Journal of Clinical Investigation.

Studies of animal models of Parkinson disease as well as clinical investigations, have shown that transplantation of fetal DA neurons can relieve the symptoms this disease. However the technical and ethical difficulties in obtaining sufficient and appropriate donor fetal brain tissue have limited the application of this therapy.

These researchers previously demonstrated that mouse embryonic stem cells can differentiate into neurons when cultured under specific conditions. These same culture conditions, technically simple and efficient, were recently applied to primate embryonic stem cells and resulted in the generation of large numbers of DA neurons. In their current JCI study, Jun Takahashi and colleagues generated neurons from monkey embryonic stem cells and exposed these cells to FGF20, a growth factor that is produced exclusively in the area of the brain affected by Parkinson disease and is reported to have a protective effect on DA neurons. The authors observed increased DA neuron development and subsequently transplanted these neurons into monkeys treated with an agent called MPTP, which is considered a primate model for Parkinson disease. These transplanted cells were able to function as DA neurons and diminished Parkinsonian symptoms.

In an accompanying commentary, J. William Langston from the Parkinson's Institute, California, describes this study as a milestone in the development of stem cell technology but cautions that while the observations are encouraging, the reported number of surviving DA neurons was very low, only 13% of the cells surviving, well below the estimated number of DA neurons that survive after fetal cell transplants (approximately 10%). While this may be a difference observed between transplantation in monkeys and humans, Langston stresses that it may be necessary for far more DA neurons to survive and for that survival to be long lasting in order to render this approach as a useful therapy in humans.

Langston highlights that "clearly the study reported here will advance research aimed at validating the use of stem cells to treat neurodegenerative disease" and this is most welcome particularly as investigators face yet another presidential moratorium endeavoring to limit the number of human stem cell lines that can be used for future research and treatment.

New route to Parkinson's found in cells' 'garbage disposal' system

Thu, 16 Dec 2004 16:49:38 PST

( from http://www.rxpgnews.com ) Researchers have known that mutations in a key gene called parkin are a major cause of Parkinson's disease (PD). Now they have discovered a new mechanism by which the parkin gene can be compromised, a finding that they say could lead to new drugs for the disorder.

Andrea Lozano, Senior Scientist at the Toronto Western Research Institute, of University Health Network and Professor of Surgery at the University of Toronto and colleagues found that the protein produced by a gene called BAG5 inhibits parkin activity and the action of another protein, called Hsp70, a "chaperone" that works with parkin. They found in studies with rats that BAG5 enhances the death of the dopaminergic neurons targeted by Parkinson's and that inhibiting the gene reduces such death.

Parkin is part of the cell's "garbage disposal" system that rids the cell of unwanted proteins by degrading them. Mutations of parkin eliminate its ability to chemically "tag" such proteins to designate them for destruction in the cell's proteasome--a process called ubiquitinylation. Loss of such ability causes such protein garbage to aggregate into lethal clumps in neurons--a hallmark of many neurodegenerative diseases. In the brain, the parkin protein works with Hsp70, which helps correct the folding of misfolded proteins.

BAG5 is one of a family of BAG proteins known to interact with other proteins to aid a variety of cell processes. The structure of BAG5 led Lozano and colleagues to explore whether it might play a role in the proteasome, along with parkin and Hsp70.

Their experiments revealed that BAG5 was activated when dopaminergic neurons were injured, suggesting a role in neurodegeneration. Experiments also revealed that BAG5 inhibits Hsp70 and interacts directly with parkin, inhibiting its activity. This inhibition, they found, enhances the formation of protein aggregates, and this formation was inhibited when the researchers shut down the activity of BAG5. In other test tube studies, the researchers also found that BAG5 inhibited parkin's ability to protect cells against proteasome dysfunction and cell death.

In experiments with rats, the researchers found that BAG5 enhanced the degeneration of dopaminergic neurons and that inhibiting BAG5 increased neuronal survival.

"Based on our findings, we propose a novel mechanism for neurodegeneration in which BAG5 interacts with both parkin and Hsp70, resulting in decreased parkin and Hsp70 function, two outcomes that are deleterious to cell survival," concluded the researchers. "Given the role of BAG5 in modulating ubiquitinylation, protein aggregation, and cell death, it may serve as a useful therapeutic target for neurodegenerative diseases such as PD."

###

The other members of the research team include Suneil K. Kalia, Sang Lee, and Li Liu, of the Toronto Western Research Institute of the University of Toronto; Patrice D. Smith, Stephen J. Crocker, and David S. Park, of the Neuroscience Research Institute of the University of Ottawa; Thorhildur E. Thorarinsdottir and Edward A. Fon, of the Centre for Neuronal Survival of McGill University; and John R. Glover, of the Department of Biochemistry of the University of Toronto. This work was supported by the Canadian Institutes of Health Research (CIHR) (S.K.K., J.R.G., E.A.F., D.S.P., A.M.L.); Michael J. Fox Foundation (T.E.T.); and Parkinson's Society of Canada (D.S.P.).

Suneil K. Kalia, Sang Lee, Patrice D. Smith, Li Liu, Stephen J. Crocker, Thorhildur E. Thorarinsdottir, John R. Glover, Edward A. Fon, David S. Park, and Andres M. Lozano: "BAG5 Inhibits Parkin and Enhances Dopaminergic Neuron Degeneration"

The context and implications of this work are discussed in a Preview by Kenny K.K. Chung and Ted M. Dawson of the Johns Hopkins University School of Medicine.

Researchers Discover Gene Mutations for Parkinson's Disease

Sat, 23 Oct 2004 15:00:38 PST

( from http://www.rxpgnews.com ) An international research team, led by scientists at the National Institute on Aging (NIA), has discovered a gene, which when mutated, causes Parkinsons disease in some families. Although Parkinsons disease is usually not inherited, the discovery of this gene and further study of how it works could open up new avenues of research for preventing or delaying the onset of the disease. In research, the study of rare familial forms of a disease has often led to major insights into the pathogenesis of more common forms.

The finding was published online by Neuron at noon ET on October 22, 2004. The collaborative work was spearheaded by Andrew Singleton, Ph.D., at the NIA, Jordi Perez-Tur of the Institut de Biomedicina de Valencia in Spain, and Nick W. Wood of the Institute of Neurology in London. The NIA is a part of the National Institutes of Health (NIH) at the U.S. Department of Health and Human Services.

"Parkinson's disease has a devastating impact upon individuals," says Elias A. Zerhouni, M.D., Director of the NIH. "This finding provides scientists with important new information about genetic mutations that underlie this disease, giving us new understanding about molecular mechanisms. Ultimately, this research will help in the development of targeted interventions that could actually alter the course of this disabling disease."

The gene, PARK8, encodes a protein named dardarin by the researchers, from the Basque word dardara, which means tremor, a major symptom of Parkinsons disease. It was isolated on chromosome 12 by investigators who studied five families with a history of Parkinsons disease who lived in the Basque region of Spain and in England. First, the group identified a small region of the chromosome 12 shared by all of the Basque families and then systematically assessed each gene in this region for mutations that might cause disease. The investigators identified two mutations in the same gene, one associated with Parkinsons disease in the Basque families and the other which was linked to the disease in the English family.

The discovery of this cluster of Basque families with Parkinsons disease helped us to narrow the genetic region we were interested in, Dr. Singleton says. Once the genes for a particular complex trait or disease, such as Parkinsons, are identified within founder populations, such as the Basques, researchers can use this information to isolate interacting genes and assess their importance in more genetically diverse cultures. Worldwide, the researchers have identified another 8 to 11 families suspected of having similar mutations, including at least one in the United States.

The investigators were brought together by Dr. Singleton to pool resources and speed the search. This was a true collaborative venture that we couldnt have done working separately, he says.

Dr. Singleton points out that other groups are working on isolating additional genes involved in the disease. There are likely other mutations in the Parkinsons disease population, he says, noting that the new data suggest that there will be mutations in typical sporadic Parkinsons disease cases in addition to those who have a family history of the disease.

About 50,000 Americans are diagnosed with Parkinson's disease each year. The disease occurs when certain nerve cells die or become impaired and can no longer produce dopamine. Without it, individuals can develop tremor or trembling in hands, arms, legs, jaw, and face; rigidity or stiffness of the limbs and trunk; bradykinesia, or slowness of movement; and postural instability or impaired balance and coordination. Patients may also have difficulty walking, talking, or completing other simple tasks. The disease is both chronic and progressive. Parkinson's disease is not usually inherited, but incidence of the disease increases with age, with an average onset at about 60 years.

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