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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
Ewen Callaway Monkeys genetically engineered to get the deadly neurological disease Huntington's could provide a unique way to test potential treatments because of their cognitive and genetic similarities to humans. "Monkey models may have a privilege over other animal models," says Anthony Chan, a biologist at Yerkes National Primate Center in Atlanta, Georgia, whose team engineered five rhesus macaque monkeys to churn out the mutant protein that causes Huntington's. Researchers routinely splice human genes in and out of mice to give them diabetes, cancer, and heart disease. But mice are of limited use when investigating brain diseases such as Huntington's: people who have it can't control their movement, speech or swallowing and their cognitive abilities deteriorate. But mice engineered to express the Huntington's protein don't jerk their muscles like humans do and it can be tough to gauge their cognitive decline. To see if primates might offer more insight, Chan's team used a virus to insert the Huntingon's gene into the DNA of 130 macaque eggs, along with a gene that makes a fluorescent green jellyfish protein. The researchers then fertilised the eggs and implanted them into eight mothers. All the monkeys born expressed the green protein, indicating that gene transfer was successful, and some already appear to have the monkey equivalent of Huntington's. The brains of one set of twins, who died a day after birth, were littered with clumps of a mutant protein found in humans with Huntington's, while the lone animal, who died a month after birth, jerked involuntarily. © Copyright Reed Business Information Ltd.
By Maggie Fox, Health and Science Editor WASHINGTON (Reuters) - More than 200 proteins are affected in Huntington's disease, researchers reported on Thursday in a study that offers scientists many potential routes to finding treatments for the fatal brain disease. Tests on fruit flies show that the mutated Huntington's protein that underlies the disease interacts with 200 other proteins, the researchers report in the Public Library of Science journal PLoS Genetics. Many of these interactions damage brain cells. "It's the gene producing something that seems to interfere with the normal activities of the cell in many, many different places and ways," Dr. Eugene Oliver, who oversees some Huntington's disease work at the National Institute for Neurological Disorders and Stroke, said in a telephone interview. Dr. Juan Botas of the Baylor College of Medicine in Houston, Texas, who worked on the study, said researchers can experiment with the proteins and the genes responsible for their production. "When you tinker with some of these genes, you find that some of them improve the symptoms. These could be potential therapeutic targets," Botas said in a statement. © 1996-2007 Scientific American, Inc
Researchers studying yeast cells have identified a metabolic enzyme as a potential therapeutic target for treating Huntington's disease, a fatal inherited neurodegenerative disorder for which there is currently no effective treatment. The group, whose results appear in the May issue of Nature Genetics, includes researchers from the University of Washington School of Medicine in Seattle and the University of Maryland School of Medicine in Baltimore. The paper was published online in advance at the journal's Web site, http://www.nature.com/ng/index.html. The group performed a genetic experiment known as a loss-of-function suppressor screen, which searches for genes that, when switched off, reduce the toxic effects of the mutant protein associated with Huntington's. One of the genes they identified encodes an enzyme, called KMO, that has been previously implicated in the disease. The enzyme functions in a metabolic pathway that is activated at early stages of the disease in people with Huntington's, as well as in animal models of the disease. "The nice thing about this finding is that there is a chemical compound available that inhibits KMO activity," said Dr. Paul Muchowski, assistant professor of pharmacology at the UW, who led the study. "We're in the midst of testing that compound in a mouse model of Huntington's disease." © 2005 University of Washington Office of News and Information
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 BP7e: 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 BP7e: 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. ¡Mira! 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.