RxPG News : Neurodegenerative Diseases

Differences in swallowing mechanism of Rett syndrome patients

Mon, 04 Aug 2008 12:48:57 PST

( from http://www.rxpgnews.com ) Researchers at Wake Forest University Baptist Medical Center have found that the reflux and swallowing problems that are common symptoms in patients with Rett syndrome and other neurological impairments, may be caused by a different mechanism than they are in healthy individuals. The finding leaves researchers to wonder if these patients truly benefit from anti-reflux surgery commonly performed in these children.

In a study published in this quarter's issue of the Journal of Applied Research, John E. Fortunato, M.D., lead researcher and an assistant professor in the Department of Pediatrics, found that the esophagus of children with Rett syndrome demonstrates different movements than it does in patients without the neurological disorder, which may explain why so many Rett patients experience persistent reflux and swallowing issues even after undergoing surgery meant to correct those problems.

"The significance of this is for other groups of patients with neurological impairment," Fortunato said. "Do all of these patients have the same mechanism for reflux and swallowing disorders? If not, performing a fundoplication (anti-reflux surgery) may not help. In fact, it may make things worse like it did in the Rett girls."

Previous studies have shown that children with neurological impairments have increased complications after anti-reflux surgery. In this study, Fortunato found the same to be true of Rett syndrome patients who underwent fundoplication. The finding leads researchers to believe that there may be something different causing the reflux and swallowing problems in Rett syndrome patients and possibly other patients with neurological impairments, such as cerebral palsy, brain injury and autism, than the accepted mechanism for the same problems in otherwise healthy adults and children.

Rett syndrome is a childhood neurodevelopmental disorder caused by mutations in the gene MECP2 located on the X chromosome. It is the only Autism spectrum disorder with a known genetic cause and is characterized by normal early development followed by loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, walking abnormalities, seizures, and mental retardation. Early symptoms may also include toe walking, sleep problems, teeth grinding, difficulty chewing and breathing difficulties while awake such as hyperventilation, apnea (breath holding), and air swallowing.

Rett syndrome affects one in every 10,000 to 20,000 live female births and is associated most closely with gastroesophageal reflux disease (GERD) and difficulty and /or pain swallowing (dysphagia). Most patients affected by the mutation have trouble eating, so they often are shorter and weigh less than other children their age. To maintain proper nutrition, some children need to be fed through tubes placed in their noses or stomachs. Boys who inherit the mutated gene usually don't survive infancy, according to the National Institute of Neurological Disorders and Stroke.

The study included 32 Rett patients between the ages of 2 and 14 with prior history of feeding problems. Researchers looked at the movement (or peristalsis) of the esophagus in the girls and found unusual esophageal movement disorders.

As a result of the study's findings, Wake Forest Baptist has approved further research to look at esophageal movement and swallowing function before and after reflux surgery, comparing children with and without neurological impairment.

"This issue is of particular interest to pediatricians who refer these patients for their 'reflux' problems," Fortunato said. "If we develop a better understanding of the mechanisms behind the problems being experienced by these children, we just might be able to find a way to make life a little more comfortable for them."

Ventricle size increase prior to Alzheimers diagnosis

Sat, 12 Jul 2008 03:51:36 PST

( from http://www.rxpgnews.com ) Researchers at Robarts Research Institute at The University of Western Ontario have found clear evidence that increases in the size of the brain ventricles are directly associated with cognitive impairment and Alzheimer’s disease.
Ventricles are fluid-filled cavities in the brain. The research, led by Robarts scientist Robert Bartha, shows the volume of the brain ventricles expands as surrounding tissue dies. The research was published online today in the neurology journal Brain.

Currently, diagnosis for Alzheimer’s relies on neuro-cognitive assessments, such as testing of memory, ability to problem solve, count, etc. Definitive diagnosis is not possible until after death when an autopsy can reveal the presence of amyloid plaques and ‘tangles’ in brain tissue.

Previous research has shown the link between ventricle size and Alzheimer’s over longer time intervals. The research conducted at Robarts Research Institute shows that ventricle size increases with mild cognitive impairment before a diagnosis of Alzheimer’s disease, and continues to increase with the onset and progression of Alzheimer’s disease after only six months.

“These findings mean that, in the future, by using magnetic resonance imaging (MRI) to measure changes in brain ventricle size, we may be able to provide earlier and more definitive diagnosis,” said Bartha, who is also an Associate Professor in the Schulich School of Medicine & Dentistry in Medical Biophysics. “In addition, as new treatments for Alzheimer’s are developed, the measurement of brain ventricle changes can also be used to quickly determine the effectiveness of the treatment.”

The research also showed that Alzheimer’s patients with a genetic marker for Alzheimer’s disease exhibited faster expansion in ventricle volume.

The research was performed by utilizing MRI scans from individuals from across North America. Graduate student Sean Nestor, a coauthor, examined 500 data sets of individuals at baseline and six months later. The images were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a large multi-site trial sponsored by the National Institutes of Health in the United States and the pharmaceutical industry. The project includes an online database of imaging information gathered from 800 people at more than 50 sites across the U.S. and Canada. The images are MRIs of individuals with no cognitive impairment, those with mild cognitive impairment and people with Alzheimer’s disease. The database can be used by any primary researcher.

One of the ADNI sites is at London’s Lawson Health Research Institute, and is led by Dr. Michael Borrie, a co-investigator on the research. Dr. Borrie is Medical Director of the Aging Brain and Memory Clinic and Geriatric Clinical Trials Group at Parkwood Hospital, St. Joseph’s Health Care, London, a Lawson researcher and Chair of the Division of Geriatric Medicine at Western’s Schulich School of Medicine & Dentistry.

Examination of the MRIs was made possible by using software developed by Cedara Software, the OEM division of Merge Healthcare. In the past, researchers would have to manually or semi-automatically trace the ventricles in many brain images, each showing a “slice” of the brain. The Merge OEM software team, led by Vittorio Accomazzi, a coauthor in the research, worked closely with the researchers to refine the software to allow the processing of large volumes of data very quickly.

"This is one of the first major research studies published using data from ADNI", said Borrie, "but there will be many more neuroimaging and biomarker discoveries to arise from the ADNI project. It is a tremendous opportunity for researchers anywhere in the world to use the ADNI databases, to collaborate and share their findings in a new way that will move Alzheimer's disease research forward more quickly, objectively and effectively. Already we are building new international collaborations, arising from ADNI, that we could not have even imagined."

Improving Cell survival in Huntington's Disease

Wed, 28 Feb 2007 13:16:00 PST

( from http://www.rxpgnews.com ) To function, each living cell needs both to build new and to degrade old or damaged proteins. To accomplish that, a number of intracellular systems work in concert to keep the cell healthy and from clogging up with damaged proteins. When proteins or peptides mutate, they can present major problems
to the clearing up of the intracellular environment. In Huntington¡¦s disease (HD) the disease provoking mutation in the huntingtin gene eventually causes the cell to build up intranuclear and cellular inclusions of protein-aggregates, made up primarily of huntingtin. One cellular organelle with a central role of clearing such protein build up in the cell is the ubiquitin proteasome system (UPS).

In Huntington¡¦s disease (HD) brains and other tissues, UPS activity is inhibited and intraneuronal nuclear protein aggregates of mutant huntingtin in HD brains indicate dysfunction of the UPS. From these results, the researchers hypothesized that enhancing UPS function would improve catalytic degradation of abnormal proteins in HD. They first genetically engineered proteasome activators involved in either non-ubiquitinated protein degradation pathways(PA28×) or subunits of PA700, the 26S proteasome ubiquitinated pathway (S5a) into transducible lentiviral vectors. To address the therapeutic hypothesis experimentally, the researchers transduced UPS subunits into HD skin fibroblasts or HD mutant protein expressing striatum-derived neurons. They determined how this intervention altered cell survival after exposure to toxins known to simulate pathological mechanisms in HD.

The manuscript shows that cellular changes due to expression of huntingtin protein with longer CAG repeats can reduce the ubiquitin proteasome system (UPS) function in Huntington¡¦s disease cells. Following compromise of the UPS, the overexpression of proteasome activator PA28×n can specifically recover proteasome function and improve cell viability in both HD model and patient cells.

These remarkable results demonstrate for the first time that it is possible to intervene therapeutically in the proteolytic pathways and organelles that participate in the specific degradation of misfolded and abnormal proteins.

3-D forms link antibiotic resistance and pantothenate kinase associated neurodegeneration

Sat, 19 Aug 2006 16:46:37 PST

( from http://www.rxpgnews.com ) The story of what makes certain types of bacteria resistant to a specific antibiotic has a sub-plot that gives insight into the cause of a rare form of brain degeneration among children, according to investigators at St. Jude Children's Research Hospital. The story takes a twist as key differences among the structures of its main molecular characters disappear and reappear as they are assembled in the cell.

The story is based on a study of the 3-D structure of an enzyme called pantothenate kinase, which triggers the first step in the production coenzyme A (CoA), a molecule that is indispensable to all forms of life. Enzymes are proteins that speed up biochemical reactions. CoA plays a pivotal role in the cells' ability to extract energy from fatty acids and carbohydrates; bacteria need CoA to make their cell walls. The job of pantothenate kinase is to grab a molecule of pantothenic acid (vitamin B-5) and another molecule that contains a chemical group called "phosphate." The enzyme then removes the phosphate group from that molecule and sticks it onto pantothenic acid.

In humans, certain mutations in this enzyme block its ability to put the phosphate group onto pantothenic acid. That diminishes the production of CoA by this route and causes the neurodegenerative disease called pantothenate kinase associated neurodegeneration (PKAN), according to Suzanne Jackowski, Ph.D., a member of the St. Jude Department of Infectious Diseases and a co-author of the paper. "We also know that certain antibiotics called pantothenamides work by impersonating vitamin B-5 and slipping into the enzyme," Jackowski said. "This blocks the bacteria's ability to produce fatty acids." The researchers already knew that different types of bacteria build their own versions of the enzyme pantothenate kinase, which are called Types I, II and III. For example, bacteria called Escherichia coli, found in the intestines and polluted water, produce Type I; Staphylococcus aureus, which causes skin infections and serious blood infections, makes type II; and Pseudomonas aeruginosa, which is an important cause of hospital-based infections, especially in burn patients, makes Type III. Types I, II and III each consist of two identical molecules called monomers, which bind together to form the enzyme. The groups had previously identified the structure and role of the Type I enzymes in pantothenamide inhibition of bacterial growth. What intrigued the St. Jude investigators now was the mystery of how Types II and III manage to do the same job even though they are constructed so differently; and why bacteria with the Type III enzyme are resistant to pantothenamide antibiotics. They also wanted to better understand the cause of PKAN in humans by comparing bacterial pantothenate kinase with the various types found in humans.

"Like all proteins, these enzymes are made up of long chains of amino acids, like beads on a string, and each type of amino acid has a unique shape and size," said Stephen White, D.Phil., chair of the St. Jude Department of Structural Biology and a co-author of the paper. The pantothenate kinase enzymes consist of two strands of amino acids that fold into various twists and turns to make a complex 3-D structure, White said. These modules, called monomers, snap together to form the enzyme. The researchers used a technique called X-ray crystallography to produce 3-D images of Types II and III and their interactions with panthothenic acid and ATP, a molecule that supplies the phosphate that the enzyme puts onto pantothenic acid.

First, the researchers crystallized a sample of the enzyme and bombarded it with X-rays using the facilities at the Argonne National Laboratory in Illinois. Then they used the pattern formed by the beams as they bounced off the crystals to create computer-generated, 3-D images of the patterns of twisting and folding amino acid chains that make up the different types of pantothenate kinase and their interactions with the other molecules.

"These images added a fascinating twist to the story of the enzymes," White said. When they studied the images, the St. Jude team realized that the monomers making up each type of enzyme were made from quite different 'strings' of amino acids. But they fold up into virtually identical looking 3-D monomers. "It was as if the uniqueness of each structure disappeared--each string folded up into the same shape as the other ones," White said. "This is very surprising because the different amino acids on each string have different sizes and different biochemical characteristics. So it would usually be impossible for them to form the same three-dimensional shapes."

But the twist to the story did not stop there. The identically shaped monomers in each pair bind to each other in novel ways to make two versions of the same enzyme that do not look alike and yet perform the same job differently. "In other words, the differences in the 'beads on a string' shapes that disappear when the strings fold into monomers suddenly reappear when the monomers combine to form even larger structures," White said. He explained that the genes for both types of enzyme evolved from a common gene ancestor. That common gene evolved so that the final Type II and III enzyme structures look and work differently, but can still do the same job--no matter what their amino acid chains look like.

"These images explained how the different types of the enzyme did the same job in different ways," said Mi Kyung Yun, M.S., research scientist in the St. Jude Structural Biology department and co-first author of the paper. "For example, the images showed that pantothenic acid binds to the Type III enzyme first, followed by ATP," said Yun, who was one of the investigators who created the X-ray crystallography images of the enzymes. "But with Type II enzyme, the ATP enters the enzyme from one direction, while pantothenic acid enters from another direction, in no particular sequence."

The images also suggested that Type II enzyme in Staphylococcus aureus has a "hole" within the loops and twists of its amino acid chains that allow pantothenamide antibiotics to slip inside the enzyme, White noted. But the Type III enzyme of Pseudomonas does not have this hole, so the antibiotic cannot slip into the enzyme. A further study confirmed that the structure of Type III made Pseudomonas resistant to the antibiotics, according to Roberta Leonardi, Ph.D., a postdoctoral fellow in Jackowski's laboratory and the paper's senior author. Leonardi removed the gene for the Type I enzyme from Escherichia coli, which is normally sensitive to the antibiotic and replaced it with the gene for the Type III enzyme used by Pseudomonas. "The gene for the Type III enzyme made Escherichia coli resistant to the antibiotics," Leonardi said. "This showed that our 3-D images of the enzymes correctly predicted that pantothenamide antibiotics couldn't get into the Type III enzyme."

In addition, test tube studies of the enzyme showed that Types I and II enzymes required different minerals than Type III in order to work. "One of the discoveries was that the Type III enzyme absolutely required potassium chloride, whereas Types I and II did not," Leonardi said. The study also showed that Type II pantothenate kinase in bacteria is similar to the human version, PanK2, according to Jackowski. Therefore, the structure of the Type II enzyme helps to explain how specific mutations in PanK2 disable this enzyme and cause the neurodegeneration disease called PKAN. "This holds promise that such insights will one day lead to the development of drugs designed to prevent or treat this disease," Jackowski said.

New biomarkers could help doctors spot neurodegenerative diseases

Mon, 14 Aug 2006 12:05:37 PST

( from http://www.rxpgnews.com ) Neurodegenerative diseases like Alzheimer's and Parkinson's in their early stages can be difficult for physicians to spot, and many diagnoses are incorrect. A finding by researchers at the University of Washington and Harborview Medical Center may soon help in the diagnosis of such diseases.

The researchers have used an advanced technique to identify proteins in the human body, known as biomarkers, that can indicate whether a patient has a particular neurodegenerative disease, or determine the progression of a disease. Searching for biomarkers is nothing new, but the researchers used a cutting-edge proteomics system, called iTRAQ, that relies on isotopic labeling of protein molecules. The system could help a physician determine the amount of a biomarker a patient may have in his body, which can help with diagnosis.

In a large multi-site study, the researchers identified more than 1,500 potential biomarkers in cerebrospinal fluid from patients with one of three neurodegenerative diseases: Alzheimer's, Parksinson's, or dementia with Lewy bodies (DLB). Researchers identified different sets of potential biomarkers corresponding to each disease; each of the proteins are linked specifically to one of the diseases. The results appear in the new issue of the Journal of Alzheimer's Disease.

"We're getting very close to being able to use these biomarkers for the clinical diagnosis of Alzheimer's and Parkinson's disease, and dementia with Lewy bodies," said the study's lead author, Dr. Jing Zhang, associate professor of pathology at the UW. His lab is at Harborview Medical Center. "This is a major improvement on other biomarker detection techniques."

Alzheimer's, Parkinson's, and other neurodegenerative diseases affect millions of people in the United States, and the toll of the diseases is expected to worsen as the Baby Boomer generation grows older. Though researchers and clinicians are learning more and more about the diseases, there is still uncertainty in the diagnosis and treatment of these conditions.

The biomarkers identified in this study need to be tested in a larger population of patients before becoming part of a full diagnostic tool, Zhang said, but these results are promising. The extensive number of proteins that the research team found in patients with neurodegenerative diseases will likely help researchers create a large panel of biomarkers that could be used in a clinical diagnosis and in monitoring disease progression.

Nitration Linked to Oxidative Stress Related Damage in Neurodegenerative Disorders

Thu, 29 Jun 2006 02:42:37 PST

( from http://www.rxpgnews.com ) Parkinson's, Alzheimer's, Lou Gehrig's disease and other brain disorders are among a growing list of maladies attributed to oxidative stress, the cell damage caused during metabolism when the oxygen in the body assumes ever more chemically reactive forms.

But the precise connection between oxidation and neurodegenerative diseases has eluded researchers. Now, a study by the Department of Energy's Pacific Northwest National Laboratory and UCLA's David Geffen School of Medicine reveals that damage is linked to a natural byproduct of oxidation called nitration.

"We looked at a healthy brain and found nitration of proteins that are implicated in neurodegenerative disease," said Colette Sacksteder, PNNL scientist and lead author of the study, published in the July issue of the journal Biochemistry (online Wed., June 28). PNNL scientist Wei-Jun Qian was co-lead author.

The results are from the most detailed proteomic analysis of a mammalian brain to date that is, a survey of nearly 8,000 different, detectable proteins in the mouse brain. The research suggests that many neurodegenerative diseases leave a biochemical calling card, or biomarker, that could be used to predict the earliest stages of brain impairment. Many biomedical researchers believe that detecting disease states before symptoms occur is the key to reversing many as-yet-incurable diseases.

The biomarker is known as nitrotyrosine, made when an amino acid in the brain, tyrosine, is in the presence of an oxidative-stress molecule called peroxynitrate. The biomarker was found on 31 sites along 29 different proteins, half of which had been previously implicated in several of the neurodegenerative diseases.

"Our study certainly suggests that the sensitivity of certain proteins to peroxynitrite is an early contributor to neurodegeneration, but other factors may also be involved," said Diana Bigelow, PNNL staff scientist and the paper's corresponding author. "The next step, of explicitly looking at tissues with neurodegenerative disease, will test this hypothesis."

REM sleep disorders can indicate early neurodegeneration

Thu, 29 Jun 2006 01:59:37 PST

( from http://www.rxpgnews.com ) The front page of the July 2006 issue of The Lancet Neurology, the journal with the highest international impact, contains a work that shows the relationship between disorders during REM sleep and future neurodegenerative pathologies. This study has been conducted by a Hospital Clínic group led by Dr. Àlex Iranzo. This study is a good example of the fact that a correct diagnosis of sleep disorders by a specialist group can achieve a high relevancy. This diagnosis is possible in the Hospital Clínic thanks to the Multidisciplinary Unit of Sleep Disorders, which is in operation since May 2003, and which consists in 17 specialists from five areas, namely, neurology, psychiatry, psychology, otorhinolaryngology, and pulmonology. This organisation permits a multidisciplinary approach with high resolution tests, department clinical protocols and sessions, with a clear optimisation of resources. The most frequent pathologies treated in this unit are sleep apnoea, snoring, REM sleep behaviour disorders, narcolepsy, night epilepsy or hypersomnia. Only last year, 3,809 visits, 1,819 sleep tests and 40 surgical interventions were made in the unit.

As well as clinical and teaching areas, this unit has high research activity as shown by the study explained below. This work has been led by Dr. Àlex Iranzo, member of the Unit of Neurology of Hospital Clínic and of the Functional Studies of the Nervous System Group of the Institut dInvestigacions Biomèdiques August Pi i Sunyer (IDIBAPS). Not only The Lancet Neurology published the work, but also it dedicates the front page to the article, and a reflection by Canadian neurologists Dr. Ronald Postuma (Department of Neurology of the Montreal General Hospital de Québec) and Dr. Jacques Montplaisir (Centre DEtude du Sommeil in the Hospital du Sacre-Coeur de Montreal).

This article is based in a descriptive study conducted since 1991 in which 44 patients from the Unit of Sleep Disorder of the Hospital Clínic were assessed. Given the low incidence of this disorder, the sample of patients studied by this Catalan group is the highest until today. All these patients presented idiopathic REM sleep behaviour disorder. These patients, usually over 60 years, suffer from unpleasant dreams and express uneasiness by screaming, crying, kicking, punching and even falling from their beds.

According to the results of this study, 20 of these patients (45%), after being correctly diagnosed in the centre and followed up during five years, developed a neurodegenerative disease. This incidence is much higher than what is expected in the general population of the same age and gender. Therefore, scientists drew the conclusion that this disorder permits the early detection of neurodegenerative diseases such as Parkinsons disease, Lewy body dementia, multiple system atrophy or mild cognitive impairment. Furthermore, the fact that the twenty patients who developed a neurodegenerative disease were those who had suffered from REM sleep behaviour disorder for the longest time, suggests that this incidence could be superior in the future.

The importance of these results lie firstly in the future possibility of administrating neuroprotective drugs to patients with the REM sleep behaviour disorder who have still not developed a degenerative disease. Furthermore, the monitoring of these patients will permit an early administration of palliative drugs, which are already available. Toward this end, the Ministry of Health has awarded this group with a FIS award named Prognostic markers of the development of a neurodegenerative disease in patients affected with REM sleep behaviour disorder.

Neurodenegerative diseases mechanisms linked to transport proteins

Fri, 09 Jun 2006 14:00:37 PST

( from http://www.rxpgnews.com ) Hampering the transport of proteins within cells may underlie several adult-onset neurodegenerative diseases, such as Huntington's, ALS and Kennedy disease. Understanding how this cell transport is blocked in these diseases may offer targets for future therapy.

In a new study published online June 4 in Nature Neuroscience, researchers from the University of Illinois at Chicago College of Medicine showed how a chemical pathway that is obstructed in Kennedy disease interferes with a cellular distribution system called "fast axonal transport" that moves proteins from where they are synthesized to where they are needed in the cell.

This transport system is critical in neurons because these cells can be as much as three feet long, says Dr. Scott Brady, professor and head of anatomy and cell biology at UIC.

"A breakdown in fast axonal transport would selectively kill neurons because neurons are especially dependent on the transport system," Brady said.

Kennedy disease is also known as spinal and bulbar muscular atrophy, or SBMA. Like the better-known ALS and Huntington's, it is a rare but devastating disease, affecting one in 40,000 people, usually between the ages of 30 and 50. Huntington's strikes about four times as many.

Neurodegenerative diseases like SBMA are caused by the lengthening of part of a gene that encodes repetitions of the amino acid glutamine in the protein. Although different genes are affected, all of the polyglutamine-expansion or "polyQ" diseases are characterized by symptoms that begin in middle age and by the loss of certain types of neurons through a pattern in which the neuron's terminals die before the cell body. PolyQ genes are expressed in many types of cells, but only neurons are affected.

Earlier studies had linked specific neurodegenerative diseases to mutations in proteins involved in intracellular transport. This led researchers to wonder if the deranged polyQ proteins inhibit fast axonal transport in several diseases, including SBMA, in which a mutation in the receptor for testosterone leads to the loss of motor neurons. In the new study, Brady and his co-workers were able to show that polyQ-AR, the mutated protein in SBMA, caused inhibition of fast axon transport by activating an enzyme called JNK that can inhibit these transport proteins.

Brady said this is the first proposed mechanism for polyQ diseases that explains why only nerve cells die and why the terminals die before the cell body. The link to the activation of the JNK enzyme suggests a new therapeutic target that might limit, delay or perhaps prevent progressive neurodegeneration, the researchers conclude.

New Tools Developed for Studying Neurodegenerative Brain Disorders

Wed, 22 Mar 2006 08:03:37 PST

( from http://www.rxpgnews.com ) Penn State researchers have created an elegantly simple model of an axon--the extension of a neuron that communicates with other neurons--and have used this model to reproduce a change in the axon's shape that is characteristic of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. This achievement is the first of its kind in a highly simplified biophysical model system. The model provides a novel avenue for investigating the specific mechanisms that contribute to complex brain diseases. It also provides a means of discovering new kinds of drugs for the treatment of these disorders.

This model, produced in the laboratory of Paul S. Weiss, Distinguished Professor of Chemistry and Physics at Penn State, has the essential features of an axon, including a lipid membrane that encloses a "cytoskeleton" scaffolding, which produces the axon's shape. The outer membrane was prepared to contain a very small amount of dye molecules that are sensitive to ultraviolet light. Shining light on the artificial axons initiated a photochemical reaction that produced highly reactive "free radicals" and triggered a catastrophic oxidative-stress reaction. The result was that the previously protruding microtubule cytoskeleton collapsed into a constricted and deformed structure resembling a string of beads--the same morphology observed during the degeneration of actual neurons.

Surprisingly, the model reproduced this highly characteristic "beading" or "pearling" even though it does not include proteins that were previously thought to be essential for causing this kind of axon destruction. "One of the beauties of a simplified model is that it allows you to ask very simple questions, which sometimes are difficult to answer in a complex living system, and sometimes to get surprising answers," Weiss said. "What makes this model so exciting is that it generates many more questions than it answers," Weiss said. "It will allow us to test hypotheses of how damage occurs, and importantly, how we might prevent it. There is a real opportunity to come up with novel therapeutic treatments."

"There is tremendous urgency right now to determine which processes cause the destructive mechanisms that we see in neurodegenerative diseases," said coauthor and Assistant Professor of Veterinary and Biomedical Sciences, Anne Milasincic Andrews. "Our study shows that oxidative stress, whatever its origin, is capable of causing the cytoskeleton of this artificial system to collapse in the same way that it does in diseased or aging brains." One of the future experiments planned by the team is to induce oxidative stress in the presence of key proteins thought to be involved in the underlying causes of the brain pathologies associated with Alzheimer's and Parkinson's diseases to see whether these proteins accelerate the damaging effects of oxidative stress.

The study also revealed many specifics about the process of axon collapse. For example, the degradation rate is faster when the lipids comprising the membrane have more multiple bonds (they are more highly unsaturated). The researchers also added free-radical scavengers, such as vitamins C, E, and K, to the model system and found that these vitamins delayed or prevented the degradation of the cytoskeleton. "These antioxidant vitamins neutralized the free radicals before they had a chance to degrade the model axon," Weiss explained.

"Simple models also allow us to build more complicated hypotheses, which later can be tested in complex living systems, such as laboratory animals. We plan to build into our model the different brain chemicals that have been implicated in neurodegenerative processes to see which are the good and bad actors--which are the most effective in promoting the radical attack from the membrane to the interior of the axon and which are the best at disabling free radicals."

One of the types of neurons that degenerate in diseases such as Alzheimer's disease and that also contribute to depression and anxiety disorders are neurons that produce the neurotransmitter serotonin. Andrews and her colleagues have made a specific model of serotonin-axon degeneration using a chemical neurotoxin. Evidence of serotonin axon damage, including beading and pearling, was published recently by Andrews and her colleagues in the journal Neuropharmacology. This study used antibodies to label serotonin axons so that the degenerative process could be visualized. The researchers injected mice with the chemical neurotoxin, 2'-NH2-MPTP, that Andrews discovered and has been studying for nearly two decades. "This latest study shows conclusively that this toxin destroys serotonin-transmitting neurons," Andrews said, "and it currently is one of the best models to destroy this type of neuron. We clearly observed evidence for axonal collapse into the beaded structures in the brains of these animals a short time after we gave them the neurotoxin."

Neurodegenerative disorders typically involve many different types of neurons that produce different neurotransmitter chemicals. "Our chemical model of neurodegeneration gives us a tool to disable just one type of neuron so we can begin to tease apart how each neurotransmitter system participates in these complex disorders," Andrews said. "We then can study the behavioral effects of the degeneration of each system and can test the effectiveness of potential therapeutics to prevent or reverse the damaging effects."

New Tools Developed for Studying Neurodegenerative Brain Disorders

Wed, 22 Mar 2006 08:03:37 PST

Research Suggests Abraham Lincoln Suffered from Spinocerebellar Ataxia type 5 (SCA5)

Fri, 03 Feb 2006 16:18:37 PST

( from http://www.rxpgnews.com ) Researchers at Johns Hopkins and the University of Minnesota have discovered a gene mutation in the descendants of Abraham Lincoln's grandparents that suggests the Civil War president himself might have also suffered from a disease that destroys nerve cells in the cerebellum-- the part of the brain that controls movement. A report on this discovery will appear in the February print issue of Nature Genetics.

The joint finding of the SCA5 mutation comes over a decade after initial speculation that Lincoln might have suffered from Marfan disease. People with this inherited disorder are often tall and thin and can commonly have slender, tapering fingers. The identification of the Marfan gene at Hopkins (Nature 352, 279-81 [1991]) sparked debate concerning testing of President Lincoln's DNA to determine whether his tall stature could have been caused by that disease.

The present discovery in Lincoln's descendants of the gene that causes a movement disorder called spinocerebellar ataxia type 5 (SCA5), however, appears to offer much stronger evidence that the past president himself might have had SCA5, according to Jeffrey D. Rothstein, M.D., Ph.D., a professor of neurology and neuroscience and vice chairman for research in the Department of Neurology at The Johns Hopkins University School of Medicine. SCAs are neurodegenerative disorders that cause loss of coordination of limbs and eye movements, slurred speech and swallowing difficulties.

"Determining President Lincoln's status relative to SCA5 would be of historical interest and would increase public awareness of ataxia and neurodegenerative disease," Rothstein said. The finding also has wider implications because similar mutations might also be associated with other neurodegenerative diseases, the Hopkins researcher said.

The researchers discovered that SCA5 is caused by a mutation of the ¥â-III spectrin gene SPTBN2, which disrupts the ability of certain nerves in the cerebellum to respond normally to incoming chemical signals. Eventually, these nerves -- called Purkinje cells -- degenerate, and the person loses fine control of the leg and arm muscles. This would explain historical descriptions of Lincoln's uneven gait -- an early sign of ataxia -- according to the researchers. Ataxia is an inability to coordinate muscle activity in the arms and legs.

"The discovery by the team of the SCA5 mutations in 90 of 299 descendants of Lincoln could enable us to prove whether Lincoln himself carried the mutation by studying genetic material obtained from artifacts containing his DNA," said Rothstein, a co-author of the Nature Genetics paper.

The researchers found the mutation in all 90 affected individuals (ages 7 to 80 at time of exam) and in 35 descendants of Lincoln who had not yet started to show symptoms of SCA5 (ages 13 to 67 at time of exam), he said. The team also found two other types of mutations in ¥â-III spectrin 2 in a French and German family, respectively. The mutations found in the American, French and German families each affected a different part of the SPTBN2 gene, and thus knocked out a different part of the ¥â-III spectrin protein.

The mutation of the SPTBN2 gene disrupts the normal shape of ¥â-III spectrin, a protein that is key to the proper functioning of Purkinje cells, according to Rothstein, who cloned the protein in 2001 and first described its role in the brain. Specifically, ¥â-III spectrin helps to anchor another protein, called "glutamate transporter EAAT4," into the membrane of the Purkinje cell.

In the current study, the investigators showed in isolated cells that EAAT4 tends to migrate rapidly through the membrane of Purkinje cells. This movement disrupts the ability of the nerve-signaling chemical glutamate to bind with EAAT4, Rothstein said. "The loss of the ability of ¥â-III spectrin to anchor EAAT4 in place so it can respond to glutamate could lead to signaling abnormalities over time," said Rothstein. "And over time, that could cause Purkinje cell death and lead to the symptoms of SCA5."

A further implication of these findings is that SCA5 mutations could affect the complex movement of proteins in other nerve cells, the researchers said. Specifically, the spectrin's interaction with a molecular "motor" that shuttles proteins through the cell suggests that mutated forms of this protein would disrupt this critical function.

The motor, which transfers proteins along cellular highways called microtubules, as well as glutamate transporters are implicated in a wide range of processes that are key to proper functioning of nerves, Rothstein noted. Disruption of the motor appears to occur in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), he added. ALS is a fatal disease involving the cells in the brain and spinal cord that control muscles. Motor disruption also occurs in Huntington's disease (HD), a genetic disorder that causes degeneration of brain cells in certain areas of the brain, resulting in uncontrolled movements, loss of intellectual abilities and emotional disturbance. In addition, disruption of protein transport through the long arms of nerves called axons occurs in Alzheimer's disease, he added.

"The results of our work and that of other researchers suggest that even though different ¥â-III spectrin mutations disrupt different cellular processes, all of these different disruptions eventually cause the death of a particular brain cell," he said. "So further studies of SCA5 will likely provide insight into molecular mechanisms common to SCA5 and other neurodegenerative diseases. In recent years we have discovered drugs that can modulate the glutamate transporter and its gene, and that research could someday be useful for treating patients with spinocerebellar ataxia."

Discovery may improve treatment of neurodegenerative diseases

Thu, 15 Dec 2005 16:13:38 PST

( from http://www.rxpgnews.com ) A team of scientists from the Universitat Autònoma de Barcelona, led by the researcher Salvador Ventura, has developed a method that allows those parts of the proteins that set off aggregation to be identified. Using this method one is able to identify the precise zones of each protein that force these proteins to bond, aggregate and form amyloid fibres. The scientists have tested the method with different proteins involved in conformational diseases, while identifying zones that were already known for their role in protein aggregation and the neurodegenerative diseases, such as Parkinson's, Alzheimer's, and forms of spongiform encephalopathy, such as mad cow disease (BSE) and its human form, Creuzfeldt-Jacob disease.

Proteins are large molecular chains that move around cells carrying vital information on the activity of the organism. The role of each protein depends largely on the form it takes, but the proteins occasionally lose this form when they collide and bind with other proteins. They aggregate, and lose their function, growing continuously to form what are known as amyloid fibres. This causes neurodegenerative diseases, such as Parkinson's, Alzheimer's, and forms of spongiform encephalopathy, such as mad cow disease (BSE) and its human form, Creuzfeldt-Jacob disease. It also produces the pancreatic malfunctions that cause type 2 diabetes.

According to Salvador Ventura, their method "identifies potential therapeutic targets against illnesses caused by protein aggregation, such as Alzheimer's, Parkinson's and type 2 diabetes. It allows a more precise identification of the targets, meaning that in theory they can be attacked more effectively".

Globular protein

The method created by the UAB researchers identifies the "hot spots" that cause protein aggregation both in globular proteins, which are folded chains, and in unfolded chains. This method may be extremely useful for designing new drugs to fight illnesses related to protein aggregation. For unfolded chains, the method can be used to design drugs that act by completely covering and shielding the "hot spots" identified through the new method so that they cannot come into contact with other proteins and aggregate. If the proteins are globular, the aggregation "hot spots" are usually protected on the inside, and are not dangerous unless they are accidentally exposed to the outside. In this case the drugs must be aimed at stabilising the structure of the protein, while preventing the "hot spots" from becoming exposed.

Possible molecular origin of nervous system degeneration diseases

Sat, 24 Sep 2005 21:06:38 PST

( from http://www.rxpgnews.com ) New research from the University of North Carolina at Chapel Hill School of Medicine points to the possible molecular origin of at least nine human diseases of nervous system degeneration.

These neurodegenerative diseases, including Huntington's disease, share an abnormal deposit of proteins inside nerve cells. This deposition of protein results from a kind of genetic stutter within the cell's nucleus asking for multiple copies of the amino acid glutamine, a building block of protein structure. These disorders are collectively known as polyglutamine diseases. Along with Huntington's, these diseases include spinobulbar muscular atrophy; spinocerebellar ataxia types 1, 2, 3, 6, 7 and 17; and dentatorubral-pallidoluysian atrophy, or Haw River Syndrome.

Haw River Syndrome is a genetic brain disorder first identified in 1998 in five generations of a family having ancestors born in Haw River, N.C. Scientists are uncertain if protein deposition causes nerve cells to deteriorate and die. This result suggests that abnormally long glutamine tracts render their host protein toxic to nerve cells.

"Polyglutamine expansion greater than 35 to 40 repeats is definitely a key player in disease etiology and, perhaps, cell death," said Dr. Nikolay V. Dokholyan, assistant professor of biochemistry and biophysics at UNC.

In their new study, Dokholyan and UNC co-authors sought to determine why a correlation exists between polyglutamine expansion length and nerve cell death, or disease. They hypothesized that expansion of glutamines results in alternative structures forming within the protein that compete with its normal structure and function.

"As a result, the protein cannot function properly and, possibly, aggregates," Dokholyan said. In other words, an abnormally long sequence of glutamines might take on a shape that prevents the host protein from "folding" or coiling into its functional three-dimensional shape. All protein molecules are simple unbranched chains of amino acids; proper folding into an intricate shape enables these molecules to perform their biological function.

Researchers used computer simulations to mimic polyglutamine behavior. The UNC study showed that when the number of glutamine repeats exceeds a critical value, the glutamines tend to take on a specific shape in the protein called a beta helix. Moreover, the tendency to form a beta helix increases as glutamine tract length becomes longer.

"In our simulations, when the length is 25 glutamines, no beta helix forms. At 45, a large majority show beta helix formation," Dokholyan said. "And it appears that 37 glutamines marks a transition, as only a small number of beta helices are formed."

"Our philosophy in general has been that many diseases have underlying molecular etiology.

MeCP2 - Rett Syndrome protein binds only to specific genes

Sun, 04 Sep 2005 07:26:38 PST

( from http://www.rxpgnews.com ) Adrian Bird of the University of Edinburgh and colleagues report today in the online issue of Molecular Cell that the "Rett Syndrome protein", MeCP2, only binds to genes with a specific sequence of nucleotide bases. This knowledge will aid in the identification of the genes that are regulated by the gene MECP2. This work was supported, in part, by the Rett Syndrome Research Foundation (RSRF).

Rett Syndrome (RTT) is a severe neurological disorder diagnosed almost exclusively in girls. Children with RTT appear to develop normally until 6 to 18 months of age, when they enter a period of regression, losing speech and motor skills. Most develop repetitive hand movements, irregular breathing patterns, seizures and extreme motor control problems. RTT leaves its victims profoundly disabled, requiring maximum assistance with every aspect of daily living. There is no cure.

The instructions needed to make the cells of all living organisms are contained in their DNA, which is organized as two complementary strands with bonds between them that can be "unzipped" like a zipper. DNA is encoded with building blocks called bases which can be abbreviated A, T, C, G. Each base "pairs up" with only one other base: A-T, T-A, C-G, G-C create the bonds that connect the complementary strands. Long stretches of base pairs make up genes.

All genes found in the human body are present in every one of our cells. What allows the same cells to develop into a heart in one instance and a kidney in another? The answer is gene expression. In a typical human cell only one tenth of the genes are expressed; the rest are shut down.

One way that genes are shut down is by attaching a small "tag" called a methyl group to the C base. The number and placement of the methyl tags dictates when a gene should be silenced. The protein, MeCP2, binds to these methyl groups to silence particular genes.

Dr. Bird and colleagues found that the methyl groups alone were not enough to attract MeCP2 to a gene. In fact, what is needed is a stretch of at least four A-T bases flanking the methyl groups.

"We previously thought that MeCP2 only needed methyl groups to bind DNA. As there are about 30 million such sites in the genome, it seemed likely that MeCP2 was a rather indiscriminate repressor of gene expression all over the genome. The new data shows that the number of potential MeCP2 binding sites is in fact far less than we thought, making it easier to find new target genes that are mis-regulated in Rett Syndrome," said Adrian Bird.

Researchers hypothesize that the devastating cascade of symptoms seen in Rett Syndrome is caused by the inability of mutated MeCP2 to silence its target genes. To date, the genes DLX5 and BDNF have emerged as strong MeCP2 target candidates and are therefore implicated in the disease process of Rett Syndrome. Interestingly, both genes were found to have the required A-T stretch, strengthening the argument that MeCP2 is involved in regulating these genes.

"Finding the MeCP2 target genes is a crucial step in understanding what goes awry in Rett Syndrome. Unfortunately these genes have been elusive. Dr. Bird's discovery of the A-T stretch provides a much-needed clue which should aid in their identification," said Monica Coenraads, Director of Research for RSRF.

Spontaneous neuronal activity is reduced in cortex in Rett Syndrome

Tue, 23 Aug 2005 21:18:38 PST

( from http://www.rxpgnews.com ) Sacha Nelson of Brandeis University in Waltham, MA and Rudolf Jaenisch of the Whitehead Institute of Biomedical Research in Cambridge, MA and their colleagues report online today in the Proceedings of the National Academy of Sciences Early Edition that spontaneous neuronal activity is reduced in the cortex of a knockout mouse model for the childhood neurodevelopmental disorder, Rett Syndrome. The Rett Syndrome Research Foundation (RSRF) and the McKnight Foundation funded this project.

Rett Syndrome (RTT) is a severe neurological disorder diagnosed almost exclusively in girls. Children with RTT appear to develop normally until 6 to 18 months of age, when they enter a period of regression, losing speech and motor skills. Most develop repetitive hand movements, irregular breathing patterns, seizures and extreme motor control problems. RTT leaves its victims profoundly disabled, requiring maximum assistance with every aspect of daily living. There is no cure.

The nervous system consists of billions of neurons that communicate with each other. Neurons don't touch and the gap between them is called a synapse. This gap is bridged by neurotransmitters that are released by the generation of electrical signals. Some neurotransmitters are excitatory and increase activity in the brain and others are inhibitory and decrease activity. In healthy brains, a balance between excitation and inhibition is essential for nearly all functions, including representation of sensory information, cognitive processes such as decision making, sleep and motor control.

The electrical signals that neurons generate can be measured using microelectrodes. Using a technique called, whole cell patch clamp, Vardhan Dani, a graduate student in Dr. Nelson's lab and Qiang Chang a post doctoral fellow from Rudolf Jaenisch's lab tested the electrical impulses in the cortex of the Rett Syndrome knockout mouse model. The cortex is one of the regions of the brain affected in patients with RTT. These mice are genetically manipulated so they lack the "Rett gene", MECP2. Like individuals with Rett Syndrome, they are seemingly normal at birth and begin to exhibit Rett-like behaviors by 5 weeks of age.

Interestingly, the groups found that the excitatory-inhibitory balance in the cortex of the mice was shifted towards inhibition (decreased brain activity). They surmise that this shift toward inhibition in the cortex and perhaps other brain regions could underlie some of the cognitive, motor, linguistic and social symptoms seen in RTT.

The spontaneous firing of L5 pyramidal neurons in 5 week-old mice was decreased 4-fold when compared to normal mice. This reduction is progressive, since two weeks earlier, in presymptomatic mice, the reduction was only 2-fold. This finding represents the first experimental evidence for a physiological abnormality that exists before symptoms appear.

"It's important to note that since this defect is seen so early it suggests that the reduced cortical activity may be a primary cellular defect that may lead to other neuropathologies," shared Qiang Chang, co-first author on the paper.

Future work will focus on elucidating the mechanisms by which the lack of MECP2 leads to increased inhibition and reduced excitation. "The next step is to use a technique called paired recording to look at the properties of individual synaptic connections between pairs of cortical neurons to find out more precisely which connections change and how. We are also trying to understand which other neural genes are regulated by Mecp2 by measuring gene expression in neurons from knockout mice and their normal siblings," said Sacha Nelson, the corresponding author of the paper.