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Gene therapy succeeds in mice with brain disease. ERIKA CHECK Gene therapy could ease the symptoms of some devastating brain disorders, according to evidence presented to US conference last week. Many neurodegenerative diseases are caused when the brain makes mutant proteins that build up in the brain, causing gradually worsening symptoms. These brain-wasting diseases are devastating and incurable. They include Huntington’s disease, which affects around 250,000 people in the United States. Beverley Davidson of the University of Iowa in Iowa City and her colleagues hope that gene therapy will help treat such diseases. The approach involves trying to correct genetic abnormalities by injecting an animal or person with corrective sequences of DNA or RNA. The researchers tested their therapy in mice with a disorder that mimics a disease called spinocerebellar ataxia type 1, which leaves sufferers progressively less able to walk. The therapy eliminated pockets of damaged brain tissue from the mice and corrected the physical symptoms of the disease. © Nature News Service / Macmillan Magazines Ltd 2004

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Link ID: 5611 - Posted: 06.24.2010

WASHINGTON, DC – Staying physically or mentally active can slow down chemical changes in the brain that lead to the neurodegeneration of Huntington’s disease, researchers show in a mouse model of the disorder. Levels of brain-derived neurotrophic factor (BDNF) stop declining when Huntington’s disease transgenic mice are housed in an enriched environment, the scientists say. BDNF promotes neuron growth and survival and can also regulate communication between neurons. “The finding that environmental enrichment increases BDNF, and that this slows disease progression, provides a potential mechanism for the effects of environmental enrichment on Huntington’s disease,” says M. Flint Beal, chair of neurology at Cornell University Medical College in New York. Copyright © 2004 Society for Neuroscience

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 5100 - Posted: 06.24.2010

DALLAS –- A test using cultured cells provides an effective way to screen drugs against Huntington's disease and shows that two compounds – memantine and riluzole – are most effective at keeping cells alive under conditions that mimic the disorder, UT Southwestern Medical Center researchers report. "These drugs have been tested in a variety of Huntington's disease models and some HD human trials and results are very difficult to interpret," said Dr. Ilya Bezprozvanny, associate professor of physiology and senior author of the study, available online and published in today's issue of Neuroscience Letters. "For some of these drugs conflicting results were obtained by different research groups, but it is impossible to figure out where the differences came from because studies were not conducted in parallel. "We systematically and quantititatively tested the clinically relevant drugs side-by-side in the same HD model. That has never been done before," said Dr. Bezprozvanny. Huntington's disease is a fatal genetic disorder, manifesting in adulthood, in which certain brain cells die. The disease results in uncontrolled movements, emotional disturbance and loss of mental ability. The offspring of a person with Huntington's have a 50 percent chance of inheriting it. More than 250,000 people in the United States have the disorder or are at risk for it. There is no cure, but several drugs are used or are being tested to relieve symptoms or slow Huntington's progression.

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 9542 - Posted: 06.24.2010

Doctors have completed the first step of a unique medical research study, evaluating 1,001 individuals at risk of developing Huntington's disease who do not know – nor do they want to know – whether they carry the genetic defect that causes the condition. An international team led by neurologist Ira Shoulson, M.D., of the University of Rochester Medical Center is trying to identify the earliest signs of the onset of the disease. The information will help clinicians design better studies of new drugs aimed at alleviating or postponing illness. It also helps researchers understand how patients evaluate potentially life-changing knowledge now available to patients through means such as genetic testing. Shoulson and colleagues from the Huntington Study Group reported their progress on the study known as PHAROS, or Prospective Huntington At Risk Observational Study, in the July issue of the Archives of Neurology. While the gene that causes the disease is known and can be identified through a blood test, fewer than one in 10 adults at risk for developing the disease have chosen to be tested. People at risk but who have not taken the test have a 50/50 chance of developing the disease. This at-risk group offers physicians a unique opportunity to witness the earliest signs of the disease, before anyone knows whether a person actually has the gene for Huntington's or not.

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 9227 - Posted: 06.24.2010

DALLAS – Researchers at UT Southwestern Medical Center have discovered that drugs commonly used to treat psychiatric illnesses and blood disorders in humans may protect the brain cells that die in people with Huntington's disease, possibly delaying the onset and slowing the progression of the disease. These findings, available online and in today's issue of Proceedings of the National Academy of Sciences, may offer new treatment options for Huntington's disease, which has no cure. Huntington's disease is a neurological disorder in which the medium spiny striatal neurons, the nerve cells that control movement and certain mental functions die. Patients die within 10-15 years after onset of the disease. The disease is caused by a mutation in the gene that makes the protein huntingtin. The mutation creates a long chain of the amino acid glutamine at one end of the protein. The length of the chain directly correlates with age of onset of the disease, with longer chains leading to symptoms earlier in life. In previous studies, Dr. Ilya Bezprozvanny, associate professor of physiology at UT Southwestern, established that one of the defects that leads to death of nerve cells with the mutant huntingtin protein is improper regulation of calcium due to errant signals in the cells. Calcium is inappropriately released from its storage area in the cells, and eventually the cells die.

Related chapters from BN: Chapter 11: Motor Control and Plasticity; Chapter 7: Life-Span Development of the Brain and Behavior
Related chapters from MM:Chapter 5: The Sensorimotor System; Chapter 4: Development of the Brain
Link ID: 6790 - Posted: 06.24.2010

MEDFORD/SOMERVILLE, Mass. – A Tufts University study has shed light on how some inherited diseases such as Huntington's and muscular dystrophy develop in humans. "Our findings show a possible reason that cells with a certain type of mutation (expansion of repetitive DNA) die prematurely," said Catherine Freudenreich, assistant professor of biology at the School of Arts and Sciences at Tufts. "We may be able to use this information to stop or slow the development of some of these degenerative diseases that affect thousands of people every year." She and her colleagues – post-doctoral fellow Mayurika Lahiri and former Tufts undergraduate researchers Tanya Gustafson and Elizabeth Majors – published their findings, "Expanded CAG repeats activate the DNA damage checkpoint pathway" in the July 23 issue of the journal Molecular Cell. Freudenreich, a molecular biologist, studies the unstable elements in the human genome, particularly the type of unstable element called "trinucleotide repeat sequences," whose expansion causes numerous human genetic diseases such as Huntington's disease (a degenerative neurological disease) and myotonic dystrophy (a type of muscular dystrophy). There are more than 15 repeat expansion diseases, all of which are of special interest because they are caused by a highly unusual DNA mutation, one in which a repetitive DNA sequence expands from a small number of copies to a larger number. For example, 20 copies of a DNA sequence (such as CAG) could expand to 70 or 100 copies to cause disease.

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 5870 - Posted: 06.24.2010

DALLAS – – Abnormally high calcium levels spurred on by a mutated gene may lead to the death of neurons associated with Huntington's disease, an inherited genetic disorder, characterized by mental and physical deterioration, for which there is no known cure. This discovery by researchers at UT Southwestern Medical Center at Dallas, published in the current issue of Neuron, sheds new light on the process that causes the selective death of neurons in the region of the brain called the striatum. Neurons in this area control emotions, body movements and several other neurological processes, including addiction. Since the discovery of the huntingtin gene (Htt) in 1993, researchers have been searching for what actually causes certain neurons to die in the striatum, leading to the disease.

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 4051 - Posted: 06.24.2010

New model for neurodegenerative disease VALERIE DEPRAETERE Researchers have used the fruit fly Drosophila melanogaster to identify the key proteins involved in the untreatable hereditary neurodegenerative disease, spinocerebellar ataxia type 1 (SCA1), which affects a couple of people in every 100,000. SCA1, a condition from the same family as Huntington's disease, is caused by mutations in the gene (called ataxin-1) that encodes the protein ataxin-1. Sufferers develop problems with their gait, speech and eyesight in middle age and become progressively more disabled from then on. Juan Botas, Huda Y. Zoghbi and their colleagues at the Baylor College of Medicine, Houston, Texas, have made a new fruitfly model of SCA1 that paves the way for the development of new therapeutic strategies1. ..... 1.Fernandez-Funez, P. et al. A genetic screen in Drosophila identifies novel suppressors and enhancers of polyglutamine-induced neurodegeneration. Nature 408, 101–106 (2000). Macmillan Magazines Ltd 2000 - NATURE NEWS SERVICE Nature © Macmillan Publishers Ltd 2000 Reg. No. 785998 England.

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 74 - Posted: 06.24.2010

Lizzie Buchen A once-promising clinical therapy for Huntington's disease needs to head back to the lab, research suggests. Huntington's disease is an inherited, untreatable and fatal disease in which patients develop severe movement and cognitive problems. One approach to treating the disease that picked up steam in the 1990s was the transplantation of healthy neural tissue from the fetuses of women who had undergone elective abortions into the patient's striatum — the brain region most severely affected in the disease. Now the results of the first long-term clinical follow-up of this approach are in1, and they don't bode well. Neurosurgeon Thomas Freeman of the University of South Florida in Tampa and his colleagues have analysed the brains of three people with Huntington's disease who received fetal striatal-tissue transplants a decade before they died. But instead of slowing or stopping the progress of the disease, the grafts degenerated even more severely than the patients' own tissue. "Based on our earlier results we were expecting that the grafts would endure," says Freeman. "This tells us we'll have to do a lot of work in the laboratory before going back to the clinic." © 2009 Nature Publishing Group,

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 13079 - Posted: 06.24.2010

By Nikhil Swaminathan Researchers have discovered early blood markers in people genetically predisposed to develop Huntington's disease, a mysterious neurodegenerative disorder. These signs may provide future targets for staving off or even preventing symptoms from developing. Huntington's disease, which affects an estimated 30,000 Americans, kills neurons (nerve cells), which leads to cognitive difficulties, a loss of movement control and emotional distress. A carrier typically does not experience symptoms until he or she is in her 30s or 40s, and lives an average of 15 to 20 years once they show up. Patients ultimately die of heart failure, pneumonia or choking triggered by the disorder. Children with a parent who has the disease have a 50 percent chance of inheriting the mutated huntingtin gene that causes it. In other neurodegenerative diseases, such as Parkinson's—which primarily affects a person's motor abilities—scientists know that nerve cells begin to die long before symptoms appear. Researchers wondered if the same was true in Huntington's. Previous research indicated this was the case in mice, but this is the first study to document presymptomatic dysfunction in humans. "In gene carriers, before they show signs of the disease, the neurodegeneration process has already started," says Sarah Tabrizi, a neurologist at University College London and coauthor of the study, which appears in The Journal of Experimental Medicine. "This indicates that the process of neuronal dysfunction which goes on to neuronal degeneration is theoretically rescuable." © 1996-2008 Scientific American Inc

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 11844 - Posted: 06.24.2010

By AMY HARMON Katharine Moser inhaled sharply. She thought she was as ready as anyone could be to face her genetic destiny. She had attended a genetic counseling session and visited a psychiatrist, as required by the clinic. She had undergone the recommended neurological exam. And yet, she realized in that moment, she had never expected to hear those words. “What do I do now?” Ms. Moser asked. “What do you want to do?” the counselor replied. “Cry,” she said quietly. Her best friend, Colleen Elio, seated next to her, had already begun. Ms. Moser was 23. It had taken her months to convince the clinic at NewYork-Presbyterian Hospital/Columbia University Medical Center in Manhattan that she wanted, at such a young age, to find out whether she carried the gene for Huntington’s disease. Huntington’s, the incurable brain disorder that possessed her grandfather’s body and ravaged his mind for three decades, typically strikes in middle age. But most young adults who know the disease runs in their family have avoided the DNA test that can tell whether they will get it, preferring the torture — and hope — of not knowing. Copyright 2007 The New York Times Company

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 10098 - Posted: 06.24.2010

Researchers have developed a fruitfly model that replicates the genetic instability seen in a variety of neurodegenerative diseases, including spinocerebellar ataxia type 3 (SCA3) and Huntington's disease. The fly model carries the same genetic mutation that affects humans who have SCA3, a disorder that causes them to lose motor coordination. The researchers believe their model will provide insight into more than 30 additional human diseases, including fragile X syndrome, that are caused by similar genetic mutations. They have already used it to better understand drugs that are now being evaluated for the treatment of these diseases. In an article published March 1, 2007, in Science Express, the advanced online publication of the journal Science, the researchers say their findings suggest those drugs may confer a therapeutic “double whammy”—alleviating two effects of the toxic protein that causes neurodegeneration. The research team was led by Howard Hughes Medical Institute researcher Nancy Bonini and colleague Joonil Jung, who are both at the University of Pennsylvania. SCA3 and Huntington's disease arise when mutations in their respective genes cause the production of an abnormally long number of repeats of three nucleotides, also known as triplet repeats. The length of the “genetic stutter” of nucleotides can vary in each disease. For this set of diseases, the repeated nucleotide triplet encodes an amino acid called glutamine, and thus leads to a protein with an abnormally long glutamine string. The malformed protein is toxic to cells and causes neurological degeneration. © 2007 Howard Hughes Medical Institute.

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 10027 - Posted: 06.24.2010

By LARRY ZAROFF, M.D. The creative process is therapeutic for many of us. If we are writers, we wrench out poetry, prose, a play about our pain, about our mistakes in life. We explain ourselves to ourselves, and generally feel better. A cousin of mine, who was made miserable by his mother, wrote her a long letter after she died. Afterward, he felt relief, unburdened. But writing is not the only way for people to unveil their troubles. Some compose music, a few paint, others choreograph or dance. Chris Furbee is making a documentary of his mother’s life, a film that powerfully reveals her gradual deterioration — physical and mental — from Huntington’s disease. In the video — some still frames from it are shown above — we see Mr. Furbee’s mother early on, before the onset of Huntington’s. She is a beautiful young woman, a fine artist. Then she is 40, in the writhing, uncooperative movements typical of Huntington’s, a personal plague like no other. Finally she is on the floor, her mental capacity gone, few words remaining. Mr. Furbee, too, has the single dominant gene for Huntington’s in every part of his body, every cell. The disease is a criminal that wants to steal his brain. It is the worst of the dementias, with its early onset and its inevitability. There is no return, no recovery. Copyright 2006 The New York Times Company

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 9620 - Posted: 06.24.2010

Huntington's Disease is a devastating inherited disorder in which brain cells are genetically programmed to degenerate. The disease, which can cause dementia, memory loss, loss of movement control, and ultimately death, can strike people as young as 30; there is currently no cure. But now, genetics researchers at the University of Iowa have shown they can rescue mice from a disease similar to Huntington's using gene therapy. Humans have two copies of most genes. Huntington's disease is one of several neurodegenerative diseases in which an error in the DNA code of just one copy of a gene causes the disease. While the normal gene tells brain cells how to build a needed protein, and the bad copy results in a toxic protein that kills brain cells. Beverly Davidson, professor of internal medicine, physiology and biophysics, and neurology at the University of Iowa, and her group treated young mice with another dominant genetic neurodegenerative disease called spinocerebellar ataxia type 1 (SCA1). They reported in the journal Nature Medicine that they treated the mice with a technique called RNA interference, or RNAi, which uses small sequences of the genetic material RNA designed to block the cell's machinery from making a protein encoded by a specific gene—in this case, halting the production of the toxic protein. The researchers used a harmless virus to carry the RNA into brain cells. © ScienCentral, 2000- 2004.

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 6014 - Posted: 06.24.2010

By Warren King Seattle Times medical reporter Huntington's disease for now has no cure. Treatment focuses on its symptoms — drugs to calm involuntary muscle movements and psychiatric problems. But researchers are homing in on a variety of therapies aimed at the underlying causes of the disease. Much attention has been focused on experiments with transplantation of fetal tissue into the brains of Huntington's patients. Small trials have shown improved cognitive function and muscle coordination in a few patients. The tissue is taken from fetuses aborted in the first trimester and implanted in damaged areas of the brain. It yields healthy brain cells to replace those killed by the disease. And the tissue is not rejected by the body, experiments by University of South Florida and French researchers have shown. Copyright © 2002 The Seattle Times Company

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 2271 - Posted: 06.24.2010

In Huntington's disease, a mutated protein in the body becomes toxic to brain cells. Recent studies have demonstrated that a small region adjacent to the mutated segment plays a major role in the toxicity. Two new studies supported by the National Institutes of Health show that very slight changes to this region can eliminate signs of Huntington's disease in mice. Researchers do not fully understand why the protein (called mutant huntingtin) is toxic, but one clue is that it accumulates in ordered clumps of fibrils, perhaps clogging up the cells' internal machinery. "These studies shed light on the structure and biochemistry of the mutant huntingtin protein and on potentially modifiable factors that affect its toxicity," said Margaret Sutherland, Ph.D., a program director at NIH's National Institute of Neurological Disorders and Stroke (NINDS). "They reveal sites within the huntingtin protein and within broader disease pathways that could serve as targets for drug therapy." Both studies were published online this week. One study, published in the Journal of Cell Biology, was led by Leslie Thompson, Ph.D., and Joan Steffan, Ph.D., of the University of California, Irvine. The other study, in Neuron, was led by X. William Yang, M.D., Ph.D., of the University of California, Los Angeles in collaboration with Ron Wetzel, Ph.D., of the University of Pittsburgh School of Medicine. The normal huntingtin protein consists of about 3,150 amino acids (which are the building blocks for all proteins). In individuals with Huntington’s disease, the mutated protein contains an abnormally long string of a single amino acid repeat; lengthier chains are associated with worse symptoms and earlier onset of the disease.

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 13627 - Posted: 06.24.2010

Just like traffic jams clog a city’s roads, sometimes proteins in our body break down and clog up our cells. As this ScienCentral News video reports, when this happens in our brain, it leads to devastating illnesses. Proteins, the basic components of all living cells, are made up of different combinations of amino acids. In order to carry out their biochemical function, each protein must first take on a particular shape, which happens when the amino acids fold into place. This delicate process of protein folding is critical, and when the amino acids do not fold correctly (i.e. "misfold"), the misshapen proteins form clumps, called aggregates, within the cell. These aggregates then start to attract other healthy proteins that are essential for cell function, which in turn bend and stop working. As this process continues, cells shut down and die, and this can lead to devastating neurodegenerative diseases like Alzheimer’s, new variant Creutzfeldt-Jakob Disease (the human form of Mad Cow Disease), and Huntington’s Disease, to name a few. © ScienCentral, 2000-2002. All rights reserved.

Related chapters from BN: Chapter 11: Motor Control and Plasticity; Chapter 16: Psychopathology: Biological Basis of Behavior Disorders
Related chapters from MM:Chapter 5: The Sensorimotor System; Chapter 12: Psychopathology: The Biology of Behavioral Disorders
Link ID: 2920 - Posted: 06.24.2010

A "molecular switch" that can prevent Huntington's disease from developing has been found in mice. A US study concluded the mutated huntingtin protein, which causes the disease, could be stopped in its tracks by a subtle chemical modification. It is hoped the work could lead to much-needed treatments for the inherited disorder. The study, by the University of California, Los Angeles, is published in the journal Neuron. It is thought between 6,000 and 8,500 people in the UK have Huntington's disease - a neurological condition that starts to show in mid-life and slowly impairs a person's ability to walk, talk and reason. Children who have one parent with the condition have a 50% chance of developing it themselves and often it is passed on before people are aware that they have it. There is no cure for the illness and treatment focuses on managing the symptoms. Although it is known that a protein mutation underpins the disease, it is not exactly clear how that mutation causes the damage seen in those with the condition. In the latest study, researchers found a small section of the mutated protein that can be modified by phosphorylation - a chemical process in the body that alters how proteins function. In mice they found blocking this phosphorylation caused the animals to develop disease symptoms. But when they tried to mimic the process the disorder did not develop. BBC © MMIX

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 13610 - Posted: 06.24.2010

THE surprising discovery that the deadly neurological disease Huntington's improves ability at some cognitive tests is helping us to understand the illness. Christian Beste from the Leibniz Research Centre for Working Environment and Human Factors in Dortmund, Germany, and his colleagues asked 13 people with Huntington's and 25 apparently healthy controls, half of whom had a gene for Huntington's but no symptoms, to judge whether tones played in a series were long or short. Huntington's worsens ability at most cognitive tests, but in this one the people with Huntington's performed better: they had an average reaction time of 0.5 seconds, compared with 0.64 seconds for the controls. They also made fewer errors (The Journal of Neuroscience, DOI: 10.1523/jneurosci.2659-08.2008). Beste has an idea why this is so. How Huntington's damages the brain is a mystery, but one explanation is that neurons become abnormally sensitive to the neurotransmitter glutamate, and eventually die off as a result. As glutamate is vital for sensory discrimination, Beste says this extra sensitivity could explain the improvements his team found. He says the finding strengthens the glutamate theory and suggests the cognitive task be used as a test for drugs that block the glutamate response. © Copyright Reed Business Information Ltd.

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 12270 - Posted: 06.24.2010

Australian researchers are using new imaging technology to provide an insight into the degenerative effect of Huntington's disease on the brain. Doctoral student India Bohanna, from the Howard Florey Institute in Melbourne, used diffusion magnetic resonance imaging technology to track the breakdown in structural connections within the brain. The research was presented at the Organization for Human Brain Mapping conference being held this week in Melbourne. Bohanna said she and her collaborators at Monash University found extensive white matter degeneration in patients recently diagnosed with Huntington's disease. The researchers used diffusion MRI, which maps the brain's white matter tracts by measuring the movement of water molecules in the tissues. White matter tracts are the connections between brain regions that allow one region to communicate with another. Bohanna said a breakdown in these structural connections disrupts the brain's communication. This could explain the motor and cognitive problems such as memory loss and clumsiness that appear as early symptoms of the onset of Huntington's disease. © Australian Broadcasting Corporation, 2008

Related chapters from BN: Chapter 11: Motor Control and Plasticity
Related chapters from MM:Chapter 5: The Sensorimotor System
Link ID: 11726 - Posted: 06.24.2010