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Clumps of defective proteins, long implicated in killing off part of the brain in Huntington's disease, may actually be helping these neurons to survive. The discovery could redirect efforts to develop treatments for Huntington's disease (HD) - a disorder that slowly kills brain cells involved in movement and higher cognitive function. HD is triggered by mutations in a protein called huntingtin which cause the protein to aggregate and ultimately form large cellular blobs known as inclusion bodies. These insoluble blobs are visible under a microscope and may contain thousands of mutant proteins. Scientists had believed that inclusion bodies help destroy neurons, since animals sick with HD have these blobs in their brain cells while healthy animals do not. And, in general, the sicker animals become with the disease, the more inclusion bodies are found in the neurons of damaged brain areas. © Copyright Reed Business Information Ltd.
By Steve Connor, Science Editor Incurable brain disorders, such as Huntingdon's disease, could soon be treated using a revolutionary technique for "switching off" disease genes. In a groundbreaking study, scientists have shown for the first time that it is possible to stop a progressive brain disease in mice with a genetic technique known as RNA interference (RNAi). The research raises the possibility of using the method to treat degenerative brain conditions such as Alzheimer's. Specialists in Huntington's a fatal inherited disease that strikes in middle age are particularly excited with the results. The latest research was carried out by a team led by Beverly Davidson of the University of Iowa who used RNAi to correct a genetic defect in mice suffering from a progressive brain disorder similar to Huntington's disease in humans. Mice with the inherited defect who were given the RNAi treatment did not develop the symptoms seen in untreated mice. Nor did the treated mice show any signs of suffering from toxic side-effects, indicating that the technique is safe. © 2004 Independent Digital (UK) Ltd
Related chapters from BP6e: 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 13: Memory, Learning, and Development
Link ID: 5926 - Posted: 06.24.2010
By Maggie Fox, Health and Science Correspondent WASHINGTON (Reuters) - Huntington's disease may be more straightforward to fight than doctors have feared, paradoxically because the genetic brain disorder is more complicated than anyone knew, U.S. researchers said on Thursday. Their research in fruit flies shows that nerve cells modify the mutated protein responsible for Huntington's disease, and this basic cell process could in theory be altered with a drug. The researchers believe their finding, published in this week's issue of the journal Science, opens a new approach to treating the fatal and incurable disease. Huntington's disease affects about 30,000 people in the United States. It is a dominant genetic defect, meaning that a child who inherits just one copy of the bad gene from a parent has a 50 percent chance of eventually developing Huntington's. It hits late in life, usually after people have had children. It causes uncontrolled movements, loss of intellectual capacity and severe emotional disturbances before killing the patient. Larry Marsh, a developmental geneticist at the University of California Irvine, has been looking for a way to fight the disease and has been focusing on just what goes wrong inside the cells carrying the mutated gene, called huntingtin, which controls production of a protein also called huntingtin. Copyright © 2004 Yahoo! Inc.
Discovery provides taste of a possible route for human drug development. HELEN R. PILCHER A simple sugar called trehalose helps to relieve the symptoms of Huntington's disease in mice. The discovery may help researchers to design drug treatments for the human condition. Huntington's disease is an inherited illness that causes profound cognitive and movement problems. It affects 1 in 10,000 people. There is currently no cure. Nobuyuki Nukina and colleagues from the RIKEN Brain Science Institute in Saitama, Japan, tested a variety of compounds on a test-tube model of the disease1. They discovered that sugar compounds seemed to have a positive effect. They then tested one specific sugar called trehalose on genetically modified mice with Huntington's disease-like symptoms. © Nature News Service / Macmillan Magazines Ltd 2004
-- Researchers at the University of California, San Diego (UCSD) School of Medicine have linked a defective protein in Huntington's disease to gridlock in the transportation system that moves signals and vital protein cargoes within the brain, eventually leading to neuron cell death. Published in the September 25, 2003 issue of the journal Neuron, their studies in Drosophila, the fruit fly, showed that a protein called huntingtin is critical for normal neuronal transportation. When the protein is defective, however, it appears to physically blocks traffic in the narrow axons that are the long pipes of the nerve cells. Although defective huntingtin genes have previously been linked to Huntington's disease, this is the first study to illustrate that the defective protein may cause neuronal damage by aggregating (sticking together) and blocking axonal traffic. Copyright © 1992-2003 Bio Online, Inc.
Huntington's disease is an inherited condition that can strike people as young as 30. Some symptoms include mood swings, depression, irritability, and involuntary movements which make it difficult for patients to drive and feed themselves. Concentration on intellectual tasks becomes increasingly difficult, and patients have trouble learning new things, remembering facts, or making decisions. "We have no cures," says Henry Paulson, associate professor of neurology at the University of Iowa School of Medicine. "It's a devastating, ultimately fatal disease." Humans have two copies of most genes. Huntington's disease is one of several degenerative diseases caused by an error in the DNA code of one copy of a gene. While the good copy tells brain cells how to build a needed protein, the bad copy results in a toxic protein that kills brain cells. © ScienCentral, 2000-2003.
-- In some genetic conditions, inheriting one bad, or mutant, gene copy from either parent is sufficient to cause disease. University of Iowa researchers have shown that it is possible to silence a mutant gene without affecting expression of the normal gene. The findings suggest that the gene-silencing technique might one day be useful in treating many human diseases, including cancer, Huntington's disease and similar genetic disorders, and viral diseases, where it would be desirable to selectively turn off certain genes that cause problems. In particular, the UI researchers were able to silence mutant genes without affecting the normal gene copy even when the mutant and the normal gene differ by as little as a single letter in the genetic code. The study will appear this week in the Online Early Edition of the Proceedings of the National Academy of Sciences (www.pnas.org). Copyright © 1992-2003 Bio Online, Inc.
Overextended polyglutamine in huntingtin protein has eclectic effects on the cell By Ricki Lewis In the late 1800s, Long Island physician George Huntington lent his name to this disorder, which is characterized by uncontrollable, dancelike movements and personality changes.6 After a long illness, individuals with HD die from complications such as choking or infection. The genetic marker discovered in 1983 had the uninspiring name G8 and the gene discovered 10 years later had the equally ineloquent IT15, for "interesting transcript 15." HD was one of the first expanded triplet repeat disorders identified, caused by extra glutamines at huntingtin's amino end. Normal huntingtin has 34 glutamine repeats and is likely antiapoptotic. Mutant proteins with more than 40 repeats cause HD. Wild-type huntingtin is cleaved and stays in the cytoplasm. Elongated, it invades the nucleus, where its effects are dual. "Mutant huntingtin enters the nucleus through pores, losing its antiapoptotic function and generating toxic products. So HD is both a gain of function through the generation of polyglutamine fragments, and a loss of antiapoptotic function," explains Michael Hayden, a professor of medical genetics at the University of British Columbia. Abnormally extended huntingtin may disable transcription factors as well as clog proteasomes. "It is becoming increasingly challenging to make sense of it all, to see all the effects of polyglutamine and to identify those important to the disease mechanism, as opposed to the so-called epiphenomena that just happen," says Kenneth Fischbeck, director of the neurogenetics division at the National Institute of Neurological Disorders and Stroke. HD may reflect an unfortunate pairing: polyglutamine is more likely to aggregate than other amino acids, and neurons are more likely to feel the effects than other cells.7,8 "Neurons appear to be exquisitely sensitive to expanded stretches of polyglutamines. This may be because they no longer divide, they have different sets of proteins expressed, and as they age, their ability to deal with cellular insults decreases," explains Larry Marsh, professor of developmental and cell biology at the University of California, Irvine.4 Adds co-author and colleague Joan Steffan, associate professor of psychiatry and human behavior, "Neurons have a different set of transcription factors expressed than other cells, and these transcription factors are more sensitive to interference by polyglutamine-containing proteins." ©2003, The Scientist Inc.
Exclusive from New Scientist Print Edition Using gene therapy to switch off genes instead of adding new ones could slow down or prevent the fatal brain disorder Huntington's disease. The method, which exploits a mechanism called RNA interference, might also help treat a wide range of other inherited diseases. "When I first heard of this work, it just took my breath away," says Nancy Wexler of Columbia University Medical School, who is president of the Hereditary Disease Foundation in New York. Though the gene-silencing technique has yet to be tried in people, she says it is the most promising potential treatment so far for Huntington's. It involves a natural defence mechanism against viruses, in which short pieces of double-stranded RNA (short interfering RNAs, or siRNAs) trigger the degradation of any other RNA in the cell with a matching sequence. If an siRNA is chosen to match the RNA copied from a particular gene, it will stop production of the protein the gene codes for (see graphic). © Copyright Reed Business Information Ltd.
A dye used for more than a century to stain autopsied brain tissue can prevent the devastating effects of Huntington's disease in mice, new research shows. The dye, called Congo red, breaks apart hallmark protein clumps in the brain, adding to evidence that these globs are to blame for symptoms of the disease. In Huntington's disease, an inherited and fatal neurological disorder, proteins called huntingtin mass together in the brain and kill neurons. However, scientists have long debated whether the proteins themselves or primarily their aggregates cause the neurological decline characteristic of Huntington's. No existing treatments can slow the disease's progression, and most victims die by midlife. Cell biologist Junying Yuan and her colleagues at Harvard Medical School in Boston were curious whether Congo red could break down aggregates of huntingtin. Other researchers had found hints in cultured cells that the commonly used dye could break apart proteins involved in related ailments such as Alzheimer's disease and prion diseases, and preliminary evidence suggested they might work against Huntington's. Yuan's team exposed human brain cells to Congo red between 6 and 48 hours after they began producing huntingtin. Adding the dye earlier caused a 60% decrease in cell death; adding it later reversed aggregation and prevented some damaging effects, like a loss of energy-producing ATP. Closer examination showed that Congo red forced protein aggregates to break apart. Copyright © 2003 by the American Association for the Advancement of Science.
Trapped proteins may explain nerve degeneration. HELEN PEARSON Many degenerative brain disorders could arise because culprit proteins are unable to escape the cell's nucleus, gathering data suggest. Messed up cell transport is increasingly suspected as a cause of disease. Proteins encoded by an abnormal string of stutter-like DNA repeats are involved in a group of neurological conditions including Huntington's disease. Scientists have scratched their heads over how the anomaly causes the nerve-cell deterioration that strikes in middle age. The proteins have lost the ability to escape the nucleus and ferry molecules elsewhere in the nerve cells, suggest Ray Truant of McMaster University in Ontario, Canada, and his colleagues. "The parallels between the diseases are starting to come together," he said at this week's American Society for Cell Biology meeting in San Francisco. © Nature News Service / Macmillan Magazines Ltd 2002
Emma Young Transplants of mouse stem cells into the brains of patients with Huntington's Chorea could help slow the associated dementia and loss of coordination, says UK company ReNeuron. It hopes to start clinical trials of the technique in the US early in 2003. Huntington's is caused by an inherited genetic mutation, which leads to a destruction of cells in a part of the brain called the striatum. ReNeuron has transplanted cells from its mouse neural stem cell line into monkeys designed to act as models of Huntington's patients. "We have shown the cell line will transplant into the monkey brain - and that it will restore function," says John Sinden, ReNeuron's chief scientist. © Copyright Reed Business Information Ltd.
Related chapters from BP6e: 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 13: Memory, Learning, and Development
Link ID: 1529 - Posted: 06.24.2010
(Ivanhoe Newswire) -- Researchers are one step closer to finding a new treatment for Huntington's disease. By improving the brain's natural protective response to Huntington's disease, researchers from Stanford University Medical Center have been able to ease the uncontrollable tremors and extend the lives of animals afflicted with the disease. Previous research shows Huntington's patients' brains become clogged with clumps of abnormal proteins called aggregates. Lead author Lawrence Steinman, M.D., from SUMC, believed preventing the proteins from clumping into aggregates could control the disease. Dr. Steinman and colleagues injected mice that had a neurological disease similar to Huntington's with a compound called cystamine. After treatment, the mice had fewer tremors and abnormal movements. Also, lifespan was increased by 20 percent in these mice. However, the amount of aggregates remained unchanged. SOURCE: Nature Medicine, 2002;8:143-149 Copyright © 2002 Ivanhoe Broadcast News, Inc.
The acetylation state of nuclear proteins could be one key to pathology and treatment By Douglas Steinberg For the first time, a study is suggesting a viable treatment to stop and even reverse Huntington's disease (HD), a lethal disorder afflicting about one of every 15,000 people. This treatment involves a class of drugs already being tested on cancer patients. Typically striking around age 40, HD causes uncontrolled movements, cognitive deficits, and emotional disturbances. Neurons degenerate in certain brain regions. The disease is inevitable if a person inherits a mutant copy of the HD gene in which the first exon contains 40 or more consecutive CAG repeats, each encoding the amino acid glutamine. According to one prominent theory, the gene product, mutant huntingtin (mHTT), folds differently than its wild-type counterpart (the function of which is unknown). As a result, mHTT is cleaved and migrates from the cell's cytoplasm to its nucleus. What happens next has become the focus of intense scrutiny because it is apparently a key to HD pathology. A recent Nature paper reported that mHTT's polyglutamine-containing region binds to the acetyltransferase domains of several transcriptional co-activator proteins and inhibits enzymatic activity.1 Ranked ninth on the Faculty of 1000's December 10th Neuroscience Top 10 list, the paper also disclosed that mHTT reduces acetylation of histones H3 and H4 in a rat cell line. Histone deacetylase inhibitors reversed that process, and when administered to Drosophila models of polyglutamine disease, these inhibitors stopped neuronal degeneration and prevented flies from dying. T S. Steffan et al., "Histone deacetylase inhibitors arrest poly-glutamine-dependent neurodegeneration in Drosophila," Nature, 413:739-43, Oct. 18, 2001. The Scientist 16:34, Jan. 21, 2002 © Copyright 2002, The Scientist, Inc. All rights reserved.
By Kim Griggs A young New Zealand scientist has managed to create the world's first large transgenic animal model for Huntington's disease, a devastating neurodegenerative disorder. For her PhD, 25-year-old Jessie Jacobsen from the University of Auckland worked out how to inject into sheep the DNA containing the gene that causes Huntington's. From 150 animals bred at a specialist research facility in South Australia, six sheep were born with the Huntington's gene; and now two are being used to breed a flock. Much of what's known about Huntington's disease comes from studies of the brains of patients who've died from the disease, but little is understood about the early stages of the disease. Huntington's disease affects one person in every 10,000 and the disease causes cell death in the brain, ultimately leading to an inability to walk, talk, think or swallow. It is an insidious disease, as for the first 30 or 40 years of a person's life, there can be no outward signs of the disease's progress. So, it is what happens in those early years that Jacobsen - and the project she is part of - aims to understand. The University of Auckland scientists decided to use sheep because their brain structure is remarkably similar to humans. They also live longer than other laboratory animals such as mice. The researchers, however, will not allow the sheep to develop the symptoms of the disease. Rather, they want to look at what is happening in the brain before symptoms occur. "They will develop the toxic protein like humans do, in exactly the same process; and then the cells will die off, hopefully in a similar pattern; and hopefully we'll be able to discover what's going on," says Jacobsen, who was named New Zealand MacDiarmid Young Scientist of the Year this week. (C) BBC
By Tom Avril It might seem hard to convince a roomful of strangers to let you gouge a few skin cells from their arms for genetic testing, especially when you are a foreigner in a poor Venezuelan community ravaged by disease, and you speak very bad Spanish. So, Nancy Wexler played her ace card. She held out her arm. A bilingual nurse then guided the American scientist through the crowd. ˇMira! the nurse said, again and again. Ella tiene la marca. "Look! She has the mark." Wexler had undergone the same skin biopsy that she was asking of the skeptical villagers. The reason, they were astonished to learn, was that she, like them, was at risk for Huntington's disease - a killer that slowly lays waste to the brain, causing its victims to speak as if they are drunk, to jerk uncontrollably, and, finally, to die. Wexler, a Columbia University neuropsychologist, is in Philadelphia this week as one of nine people being honored by the Franklin Institute for achievement in science and technology. Other winners of the prestigious awards range from a native of Wenonah, Gloucester County, who is the lead scientist on NASA's Mars Rover mission, to an IBM engineer whose work transformed computers.
ATLANTA - The severe neurodegeneration associated with Huntington's disease may result from molecular mutations that block the transport of nutrients within cells. Findings from the Emory University School of Medicine indicate that the mutant huntingtin protein limits the efforts of the huntingtin-associated protein-1 (HAP1) to provide nutrients to growing neurons, or neurites. Without those nutrients, neurites fail to develop and mature neurons degenerate. Huntington's disease was first identified more than 125 years ago, and often inhibits speech, movement, reasoning and memory. The result of an abnormal Huntington gene, the hereditary disorder is estimated to affect one out of every 10,000 people. Though some current pharmacological treatments do address symptoms, scientists have been unable to stop the disease's progression. However, scientists at Emory are making headway in the search for a cure. The findings that appear in the May 31 issue of the Journal of Neuroscience are the latest of more than a decade of Huntington's disease-related discoveries led by Xiao-Jiang Li, PhD, professor of human genetics at Emory University School of Medicine. Juan Rong, doctoral student in the neuroscience graduate program at the Emory University School of Medicine, is the lead author of the article. The senior author, Dr. Li, first discovered the protein HAP1 as a postdoctoral fellow in 1995. In previous articles, he has identified the importance of HAP1 to the normal functioning of the hypothalamus, a region of the brain that acts as a central switchboard to regulate feeding and other body functions.
CAMBRIDGE, Mass.--Researchers at MIT and Harvard Medical School have identified a compound that interferes with the pathogenic effects of Huntington's disease, a discovery that could lead to development of a new treatment for the disease. There is no cure for Huntington's, a neurodegenerative disorder that now afflicts 30,000 Americans, with another 150,000 at risk. The fatal disease, which is genetically inherited, usually strikes in midlife and causes uncontrolled movements, loss of cognitive function and emotional disturbance. "There are now some drugs that can help with the symptoms, but we can't stop the course of the disease or its onset," said Ruth Bodner, lead author on a paper appearing online the week of Mar. 6 in the Proceedings of the National Academy of Sciences (PNAS). Bodner is a postdoctoral fellow in MIT's Center for Cancer Research. The compound developed by Bodner and others in the laboratories of MIT Professor of Biology David Housman, Harvard Medical School Assistant Professor Aleksey Kazantsev and Harvard Medical School Professor Bradley Hyman might lead to a drug that could help stop the deadly sequence of cellular events that Huntington's unleashes. "Depending on its target, any one compound will probably block only a subset of the pathogenic effects," Bodner said.
Howard Florey Institute scientists in Melbourne have found that fluoxetine (commonly marketed as Prozac®) not only improves depression in Huntington's disease, but also improves learning and memory. Dr Anthony Hannan and his team also found that fluoxetine restores the brain's process of neurogenesis - the birth of new neurons - to normal levels, which helps delay the onset of the inherited fatal disease. People with Huntington's disease have progressive motor problems, cognitive deficits (dementia) and psychiatric symptoms (the most common is depression) that usually start to appear in mid-life. There is no cure and death usually results within 10 to 20 years of symptom onset, or faster in the childhood-onset form of the disease. The disease is caused by a mutation in a single gene and when this defective gene is passed from parent to child, 50 percent of the offspring will inherit the disorder, which can be detected by genetic testing. Dr Hannan said this discovery was an important step in developing effective treatments to delay the onset of symptoms and the progression of Huntington's disease. "Now that we've found fluoxetine improves memory problems, or dementia, as well as depression in mice with Huntington's disease, further research can be conducted to see if the drug has the same benefits in humans with the disease," Dr Hannan said.
Related chapters from BP6e: 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: Biological Basis of Behavioral Disorders
Link ID: 8007 - Posted: 10.07.2005
CHAPEL HILL -- 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. The findings are currently in PLoS Computational Biology, an open-access journal published by the Public Library of Science (PloS) in partnership with the International Society for Computational Biology. 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. The disorder begins in adolescence (between ages 15 and 30 years) and is characterized by progressive and widespread damage to brain function, leading to loss of coordination, seizures, paranoid delusions, dementia and death within 15 to 20 years.