Category: Huntington’s Disease

Scientists at Melbourne's Howard Florey Institute have discovered that mental and physical stimulation delays the onset of dementia in the fatal genetic disease, Huntington's disease.

This Australian research opens up new therapeutic possibilities for other devastating and difficult to treat brain diseases, including Alzheimer's disease where dementia is a key component.

The Florey's Dr Jess Nithianantharajah and Dr Anthony Hannan showed mice with the Huntington's disease gene displayed impairments on learning and memory tests at an early stage of the disease, prior to the obvious signs of movement problems. This closely correlates with observations in Huntington's disease patients.

However, Dr Jess Nithianantharajah said by providing the mice with an enriched environment that enhanced their mental and physical stimulation, the mice performed better on these memory tests.

"This discovery is quite remarkable because we have shown that an enriched environment not only delayed the onset of dementia, but it also slowed the progression of memory loss in these mice," Dr Jess Nithianantharajah said.

"We also showed that in the Huntington's disease mice, specific molecular changes occur that relate to communication between brain cells (synapses) in a region of the brain called the hippocampus, which plays a significant role in the formation of memories.

"The Huntington's disease mice without increased mental and physical activity showed decreased levels of specific proteins that are expressed at the synapse, which are essential for normal brain function.

"But the Huntington's disease mice exposed to increased mental and physical activity did not show this decrease," she said.

Huntington's is a very powerful model for nature-versus-nurture investigations. This discovery implies that gene-environment interactions and how they affect changes in the brain's pathways is important for all brain diseases.

Treatments for complex psychiatric disorders, like depression and schizophrenia, may also benefit from these research efforts.

This research was recently published in the international Journal of Neurobiology of Disease and involved collaborations between the Howard Florey Institute and the University of Melbourne.

Huntington's disease is an inherited disease that affects specific areas of the brain. It is caused by a mutation in a single gene and is inherited by 50 percent of the offspring of patients. A common symptom is the jerky movement of the arms and legs, known as 'chorea', but patients also have difficulties with concentration and memory, as well as psychiatric symptoms such as depression. These symptoms gradually become more severe over the years, inevitably leading to death.

Scientists at the Weizmann Institute have proposed a mechanism that provides an explanation for the remarkable precision of the genetic time bomb causing Huntington’s and other trinucleotide repeat diseases. Huntington’s disease is a genetic time bomb: Programmed in the genes, it appears at a predictable age in adulthood, causing a progressive decline in mental and neurological function and finally death. There is, to date, no cure.

Huntington’s and a number of diseases like it, collectively known as trinucleotide repeat diseases, are caused by an unusual genetic mutation: A three-letter piece of gene code is repeated over and over in one gene. Scientists at the Weizmann Institute have now proposed a mechanism that provides an explanation for the remarkable precision of the time bomb in these diseases. This explanation may, in the future, point researchers in the direction of a possible prevention or cure.

The number of repeats in Huntington’s patients ranges from 40 to over 70. Scientists have noted that, like clockwork, one can predict – by how many times the sequence repeats in a patient’s gene – both the age at which the disease will appear and how quickly the disease will progress. The basic assumption has been that the protein fragment containing the amino acid (glutamine) encoded in the repeating triplet slowly builds up in the cells until eventually reaching toxic levels.

This theory, unfortunately, fails to explain some of the clinical data. For instance, it doesn’t explain why patients with two copies of the Huntington’s gene don’t exhibit symptoms earlier than those with a single copy. Plus, glutamine is produced in only some trinucleotide diseases, whereas the correlation between sequence length and onset age follows the same general curve in all of them, implying a common mechanism not tied to glutamine.

Research student Shai Kaplan in Prof. Ehud Shapiro’s lab in the Biological Chemistry Department and the Computer Sciences and Applied Mathematics Department realized the answer might lie in somatic mutations – changes in the number of DNA repeats that build up in our cells throughout our lives. The longer the sequence, the greater the chance of additional mutation, and the scientists realized that the genes carrying the disease code might be accumulating more and more DNA repeats over time, until some critical threshold is crossed.

Based on the literature on some 20 known trinucleotide repeat diseases and their knowledge of the mechanisms governing somatic mutation, Shapiro, Kaplan (who is also in the Molecular Cell Biology Department), and Dr. Shalev Itzkovitz created a computer simulation that could take a given number of genetic repeats and show both the age of onset and the way in which the disease progresses.

The new disease model appears to fit all of the facts and to provide a good explanation for the onset and progression of all of the known trinucleotide repeat diseases. Experimentation in research labs could test this model, say the scientists and, as it predicts that all these diseases operate by somatic expansion of a trinucleotide repeat, it also suggests that a cure for all might be found in a drug or treatment that slows down the expansion process.

Prof. Ehud Shapiro’s research is supported by the Clore Center for Biological Physics; the Arie and Ida Crown Memorial Charitable Fund; the Cymerman – Jakubskind Prize; the Fusfeld Research Fund; the Henry Gutwirth Fund for Research; Ms. Sally Leafman Appelbaum, Scottsdale, AZ; the Louis Chor Memorial Trust Fund; and the estate of Fannie Sherr, New York, NY. Prof. Shapiro is the incumbent of the Harry Weinrebe Chair of Computer Science and Biology.

These findings were recently presented in PLoS Computational Biology.

Although repeating sequences of three nucleotides encoding some of the bodies' 20 amino acids are a normal part of protein composition, abnormal expansion of trinucleotide repeats is the known cause of multiple inherited neurodegenerative disorders, including Huntington disease.

Scientists at Emory University School of Medicine, in research with mice, now have discovered more specific information about how this inherited expansion of a normal repeated DNA sequence alters gene expression.

The inherited diseases caused by an abnormal number of glutamine repeats (generally, more than 37) are known as polyglutamine, or PolyQ diseases. The diseases lead to a progressive degeneration of nerve cells usually affecting people later in life. Although these diseases share the same abnormal expansion of the repeated glutamine sequence and some symptoms, the repeats for the different PolyQ diseases occur in genes on different chromosomes.

The scientists found that abnormal glutamine repeats interfere with the function of an essential transcription factor called TBP (TATA-box binding protein). In turn, the expanded polyQ sequence alters the interaction of TBP with other transcription factors, leading to neurodegeneration. Transcription is the process by which the genetic code in the DNA sequence is first transcribed into RNA. The RNA is subsequently translated into a protein.

"Our study has a broad impact for understanding transcriptional regulation of gene expression as well as the pathogenesis of neurodegeneration caused by expanded polyglutamine proteins," says Xiao-Jiang Li, MD, PhD, Distinguished Professor of Human Genetics in Emory University School of Medicine and the paper's senior author.

The research is reported online in the journal Nature Neuroscience.

Lead author was Meyer J. Friedman, a graduate student in Emory's Department of Human Genetics. Other Emory authors were Anjali G. Shah, Zhi-Hiu Fang, Elizabeth G. Ward, Stephen T. Warren and Shihua Li.

The research was funded by the National Institutes of Health.

MassGeneral Institute for Neurodegererative Disorders (MIND) researchers have identified a compound that may lead to a treatment that could protect against the effects of Huntington's Disease (HD). Their report, which will appear in the Proceedings of the National Academy of Sciences, describes how a small molecule called C2-8 appears to delay the loss of motor control and reduce neurological damage in a mouse model of the disorder. 

"We found that C2-8 slows the progress of HD in a mouse model and might do the same thing in human patients, if it or its biochemical relatives can be translated into a drug," says Steven Hersch, MD, PhD, of MIND and the Massachusetts General Hospital (MGH) Department of Neurology, who led the study. "What we don't know yet is precisely how it works, what molecules it interacts with in cells and how potent it might be."

C2-8 was first identified as a candidate treatment for HD by MIND researcher Aleksey Kazantsev, PhD, based on its ability to block the aggregation of the mutant huntingtin protein in yeast and animal tissue and to improve function in a fruit fly model. The current study was designed to further investigate its potential as a therapeutic drug. The researchers first confirmed that oral doses of C2-8 can cross the blood-brain barrier and are nontoxic in a mouse model of HD. They also found that C2-8 does not interact with a number of molecules predictive of negative side effects.

HD mice that were treated with C2-8 starting at the age of 24 days scored significantly better on tests of strength, endurance and coordination than did HD mice that did not receive the molecule. While treatment significantly delayed progressive motor disability, the animals receiving C2-8 did not live longer. Examination of brain cells from the striatum, the area of the brain where the deterioration of HD occurs, showed that treated mice had less shrinkage of brain cells and smaller aggregates of huntingtin protein than did untreated HD mice.

"We've both validated that compounds reducing the aggregation of mutant huntingtin are potential HD drugs — so that strategy is one that other scientists should pursue — and shown that C2-8 has potential as the basis of a neuroprotective treatment," says Hersch. "We now need to confirm those results in a different mouse model, see whether similar compounds may be more potent than C2-8 and search for the enzyme or receptor it is binding to." Hersch is an associate professor of Neurology at Harvard Medical School.

Vanita Chopra, PhD, and Jonathan Fox, PhD, of MIND and MGH-Neurology are co-first author of the PNAS study. Additional co-authors are Greg Lieberman, Kathryn Dorsey, Kazantsev and Anne B. Young, MD, PhD, of MIND/MGH-Neurology; Wayne Matson, PhD, Boston University School of Medicine; Peter Waldmeier, PhD, Novartis Institute for Biomedical Research, Basel, Switzerland; and David Houseman, PhD, Massachusetts Institute of Technology. The study was supported by the Discovery of Novel Huntington's Disease Therapeutics Fund, MIND and the Massachusetts General Hospital.

For years researchers in neurology have believed that people with Huntington's disease have more children than the general population because of behavioral changes associated with the disease that lead to sexual promiscuity.

In a new Tufts University study, three biologists have challenged that notion by suggesting that people with Huntington's have more children because they are healthier – not more promiscuous – during their peak reproductive years.

"Huntington's is a disease that may have beneficial health effects on people early in life, but dire health costs later when symptoms express themselves," said Philip T. Starks, assistant professor of biology in the School of Arts and Sciences at Tufts. "Ironically, these early health benefits may contribute to an increased prevalence of the disease." Huntington's disease is a genetic disease involving degeneration of the central nervous system (CNS), leading to uncontrolled muscle movements, emotional instability and dementia.

Folk musician and songwriter Woody Guthrie died from complications of the disease in 1967.

Link between Huntington's and immune system

Along with Dr. Starks, former Tufts undergraduate Benjamin R. Eskenazi and present doctoral student Noah S. Wilson-Rich reviewed 75 published studies in forming their hypothesis. They focused on the tumor suppressor protein p53, which maintains normal cell growth and is found at levels above normal in Huntington's sufferers.

At these elevated levels, p53 appears to increase resistance to cancer by causing cancerous cells to destroy themselves. Previous research has linked increased production of p53 to the mutant form of the Huntington (htt) protein that is found in the CNS of individuals with the disease. In this new hypothesis, the Tufts researchers suggest that p53 not only reduces the incidence of cancer in those affected by Huntington's disease but by improving overall health may also contribute to increased offspring production.

The Tufts team analyzed the often-noted fertility gap between people who have Huntington's and those who do not. Studies comparing family members indicated that individuals with the disease had between 1.14 and 1.34 children for every child born to an unaffected sibling. In explaining this difference, previous researchers have theorized that psychological deterioration and difficulty in discriminating between right and wrong – both symptoms associated with Huntington's — are reasons for promiscuous behavior in people who had the disease. But Eskenazi, Wilson-Rich and Starks observed that such behavior takes place later in life — not during peak reproductive age. They noted that the onset of Huntington's disease occurs, on average, at 41.5 years of age.

In their alternative hypothesis the Tufts researchers suggested that individuals affected with Huntington's have better health earlier in life at the time when their fertility is highest. "We've raised the possibility that the high birth rates are a result of better health," explained Starks. "We know that healthy people have more offspring than those who are sick."

Starks and his team suggested that one key factor behind these health benefits may be p53, and pointed to a 1999 study by doctors at the Danish Huntington Disease Registry at the University of Copenhagen that found lower age-adjusted cancer rates for individuals affected by Huntington's.

"Research has shown that individuals with Huntington's produce higher levels of cancer-suppressing p53, and we hypothesize that they may also reap the health benefits associated with a generally more vigilant immune system," said Starks. "These individuals also suffer from the negative impacts of heightened immune function, as they are more likely than those without Huntington's to suffer from autoimmune diseases."

Starks said that the hypothesis pointing to health benefits of people with Huntington's requires significant additional research. "This is a hypothesis that still needs strong support through more studies," he said.

Marriage of evolutionary biology and medicine

Starks, whose research areas include behavior and evolution in a wide range of organisms, noted that Huntington's disease may be an example of antagonistic pleiotropy, in which one gene creates multiple and conflicting effects. Another example of this phenomenon includes a gene that appears to decrease the incidence of Alzheimer's disease while increasing the chance of elevated lipids in the blood. The convergence of evolutionary biology and medicine can reap many benefits, he believes. "This marriage has already shed light on phenomena such as fever and morning sickness," he noted. Huntington's disease may be one more beneficiary of this synergy.

Reference: "A Darwinian Approach to Huntington's Disease: Subtle Health Benefits of a Neurological Disorder" is published in the August 8, 2007 online issue of the journal Medical Hypothesis and will soon appear in print.

Paying close attention to how a canary learns a new song has helped scientists open a new avenue of research against Huntington's disease — a fatal disorder for which there is currently no cure or even a treatment to slow the disease.

In a paper published Sept. 20 in the Journal of Clinical Investigation, scientists at the University of Rochester Medical Center have shown how stem-cell therapy might someday be used to treat the disease.

The team used gene therapy to guide the development of endogenous stem cells in the brains of mice affected by a form of Huntington's. The mice that were treated lived significantly longer, were healthier, and had many more new, viable brain cells than their counterparts that did not receive the treatment.

While it's too early to predict whether such a treatment might work in people, it does offer a new approach in the fight against Huntington's, says neurologist Steven Goldman, M.D., Ph.D., the lead author of the study. The defective gene that causes the disease has been known for more than a decade, but that knowledge hasn't yet translated to better care for patients.

"There isn't much out there right now for patients who suffer from this utterly devastating disease," said Goldman, who is at the forefront developing new techniques to try to bring stem-cell therapy to the bedside of patients. "While the promise of stem cells is broadly discussed for many diseases, it's actually conditions like Huntington's — where a very specific type of brain cell in a particular region of the brain is vulnerable — that are most likely to benefit from stem-cell-based therapy."

The lead authors of the latest paper are Abdellatif Benraiss, Ph.D., research assistant professor at the University, and former post-doctoral associate Sung-Rae Cho, Ph.D., now at Yonsei University in South Korea.

The latest results have their roots in research Goldman did more than 20 years ago as a graduate student at Rockefeller University. In basic neuroscience studies, Goldman was investigating how canaries learn new songs, and he found that every time a canary learns a new song, it creates new brain cells called neurons. His doctoral thesis in 1983 was the first report of neurogenesis — the production of new brain cells — in the adult brain, and opened the door to the possibility that the brain has a font of stem cells that could serve as the source for new cells.

The finding led to a career for Goldman, who has created ways to isolate stem cells. These techniques have allowed Goldman's group to discover the molecular signals that help determine what specific types of cells they become, and re-create those signals to direct the cells' development. Benraiss has worked closely with Goldman for more than 10 years on the Huntington's project.

"The type of brain cell that allows a canary to learn a new song is the same cell type that dies in patients with Huntington's disease," said Goldman, professor of Neurology, Neurosurgery, and Pediatrics, and chief of the Division of Cell and Gene Therapy. "Once we worked out the molecular signals that control the development of these brain cells, the next logical step was to try to trigger their regeneration in Huntington's disease."

Huntington's is an inherited disorder that affects about 30,000 people in the U.S. A defective gene results in the death of vital brain cells known as medium spiny neurons, resulting in involuntary movements, problems with coordination, cognitive difficulties, and depression and irritability. The disease usually strikes in young to mid adulthood, in a patient's 30s or 40s; there is currently no way to slow the progression of the disease, which is fatal.

Stem cells offer a potential pool to replace neurons lost in almost any disease, but first scientists must learn the extensive molecular signaling that shapes their development. The fate of a stem cell depends on scores of biochemical signals — in the brain, a stem cell might become a dopamine-producing neuron, perhaps, or maybe a medium spiny neuron, cells that are destroyed by Parkinson's and Huntington's diseases, respectively.

To do this work, Goldman's team set up a one-two molecular punch as a recipe for generating new medium spiny neurons, to replace those that had become defective in mice with the disease. The team used a cold virus known as adenovirus to carry extra copies of two genes into a region of the mouse brain, called the ventricular wall, that is home to stem cells. This area happens to be very close to the area of the brain, known as the neostriatum, which is affected by Huntington's disease.

The team put in extra copies of a gene called Noggin, which helps stop stem cells from becoming another type of cell in the brain, an astrocyte. They also put in extra copies of the gene for BDNF (brain-derived neurotrophic factor), which helps stem cells become neurons. Basically, stem cells were bathed in a brew that had extra Noggin and BDNF to direct their development into medium spiny neurons.

The results in mice, which had a severe form of Huntington's disease, were dramatic. The mice had several thousand newly formed medium spiny neurons in the neostriatum, compared to no new neurons in mice that weren't treated, and the new neurons formed connections like medium spiny neurons normally do. The mice lived about 17 percent longer and were healthier, more active and more coordinated significantly longer than the untreated mice.

The experiment was designed to test the idea that scientists could generate new medium spiny neurons in an organism where those neurons had already become sick. Now that the capability has been demonstrated, Goldman is working on ways to extend the duration of the improvement. Ultimately he hopes to assess this potential approach to treatment in patients.

"This offers a strategy to restore brain cells that have been lost due to disease. That could perhaps be coupled with other treatments currently under development," said Goldman. Many of those treatments are being studied at the University, which is home to a Huntington's Disease Center of Excellence and is the base for the Huntington Study Group.

In addition to Benraiss, Cho, and Goldman, other authors include former Cornell graduate student Eva Chmielnicki, Ph.D.; Johns Hopkins neurosurgeon Amer Samdani, M.D., now at Shriners Children's Hospital in Philadelphia; and Aris Economides of Regeneron Pharmaceuticals. The work was funded by the National Institute of Neurological Disorders and Stroke, the Hereditary Disease Foundation, and the High Q Foundation.

A major breakthrough in the understanding and potential treatment of Huntington's disease* has been made by scientists at the University of Leeds .

Researchers in the University's Faculty of Biological Sciences have discovered that one of the body's naturally occurring proteins is preventing 57 genes from operating normally in the brains of Huntington's sufferers. In addition, the destructive nature of this protein could potentially be halted using drugs that are already being used to help cancer patients.

“This is a really exciting breakthrough,” says researcher Dr Lezanne Ooi. “It's early days, but we believe our research could lead to radical changes in treatment for Huntington 's sufferers. The fact that these cancer drugs have already been through the clinical trials process should speed up the time it takes for this research to impact directly on patients.”

Huntington 's is an inherited degenerative neurological disease that affects between 6500 and 8000 people in the UK and up to 8 people out of every 100,000 in Western countries. Any person whose parent has Huntington 's has a 50-50 chance of inheriting the faulty gene that causes it and everyone with the defective gene will, at some point, develop the disease.

It is characterised by a loss of neurons in certain regions of the brain and progressively affects a sufferer's cognition, personality and motor skills. In its later stages, sufferers almost certainly require continual nursing care. Secondary diseases, such as pneumonia are the actual cause of death, rather than the disease itself.

Dr Ooi's research has identified the effects of one of the body's proteins on the neurons of Huntington 's sufferers. Neurons are usually protected by the protein BDNF (brain derived neurotrophic factor), whose many functions also include encouraging the growth and differentiation of new neurons and synapses. However, in Huntington 's sufferers, the repressor protein known as REST – which is usually found only in certain regions of the brain – enters the nucleus of the neuron and decreases the expression of BDNF.

She has also been studying some of the enzymes which assist the function of this protein. It is these enzymes that provide the mechanism for the protein to wreak havoc in the brains of Huntington's sufferers, and that are already being targeted in certain cancer drugs.

Currently, the symptoms of Huntington 's can be managed through medication to help with loss of motor control and speech therapy but there is no definitive treatment. This research provides a first step in developing a treatment regime that may halt the onset of the disease.

“Huntington's is a devastating illness that affects whole families. Those who know they've inherited the faulty gene live in a shadow of uncertainty over how long their symptoms start to develop. It can also be particularly cruel since every child born to a parent that has the HD gene is at 50% risk of having inherited the gene,” says Cath Stanley, Head of Care Services at the Huntington's Disease Association.

“As such, any developments in the understanding of this disease are welcome, but this breakthrough is particularly exciting as it opens up an avenue for researching a possible treatment using drugs that are already available, rather than starting from scratch.”

Dr Ooi's research was funded by The Wellcome Trust and carried out in collaboration with the University of Milan and King's College London. The paper has been published in the Journal of Neuroscience.

*Huntington 's is caused by the insert of an extra sequence in one gene on chromosome 4 – longer inserts correlate with greater severity of the disease. The insert is called a polyglutamine tract and it occurs in the Huntingtin [correct] protein.

McMaster University researchers have first insight into how Huntington's disease (HD) is triggered. The research will be published online in the British Journal, Human Molecular Genetics, on August 20.

"These are exciting results by the McMaster team," said Dr. Rémi Quirion, Scientific Director at the Canadian Institutes of Health Research, Institute of Neuroscience, Mental Health and Addiction. Even if the huntingtin protein has been known for almost 20 years, the cause of Huntington's disease is still not clear. Data reported here shed new lights on this aspect and possibly leading to new therapeutic potential in the future."

Ray Truant, professor in the Department of Biochemistry and Biomedical Sciences, has been studying the biological role of the huntingtin protein and the sequences in the protein that tell it where to go within a brain cell.

Huntington disease (HD) is a neurological disorder resulting from degeneration of brain cells. The degeneration causes uncontrolled limb movements and loss of intellectual faculties, eventually leading to death. There is no treatment. HD is a familial disease, passed from parent to child through a mutation in the normal gene. The disorder is estimated to affect about one in every 10,000 persons.

Truant and PhD candidate graduate student, Randy Singh Atwal, have discovered a small protein sequence in huntingtin that allows it to locate to the part of the cell critical for protein quality control. Similar findings have been seen to be very important for other neurodegenerative diseases such as Parkinson's and Alzheimer's diseases.

Huntingtin protein is essential for normal development in all mammals, and is found in all cells, yet its function was unknown. It appears that huntingtin is crucial for a brain cell's response to stress, and moves from the endoplasmic reticulum into the nucleus, the control centre of the cell. When mutant huntingtin is expressed however, it enters the nucleus as it should in response to stress, but it cannot exit properly, piling up in the nucleus and leading to brain cell death in HD.

"What is important to Huntington disease research is that in the learning of the basic cell biology of this protein, we have also uncovered a new drug target for the disease," says Atwal.

Atwal additionally found that huntingtin can be sent to the nucleus by protein modifying enzymes called kinases, and he has determined the three-dimensional shape of this sequence.

Truant and Atwal's work indicates that if mutant huntingtin is prevented from entering the nucleus, it cannot kill a brain cell. This means that a kinase inhibitor drug may be effective for Huntington's disease. Kinase inhibitors form the largest number of successful new generation drugs that are coming to market for a plethora of diseases including stroke, arthritis and cancer.

"This is most exciting to us, because we immediately have all the tools and support in hand at McMaster to quickly hunt this kinase down, and find potential new drugs for Huntington's disease in ways that are similar or better than a large pharmaceutical company", says Truant. Truant's lab is also collaborating in the US with the Cure Huntington's Disease Initiative (CHDI) a novel, non-profit virtual pharmaceutical company focused on HD.

A large portion of this work was completed in the new McMaster biophotonics facility, and additional research will be done in McMaster's unique high throughput screening lab and other new labs being established at the University.

"We can actually watch huntingtin protein move inside of a single live brain cell in real time in response to stress, and we can watch mutant huntingtin kill that cell, even over days," says Truant. "Using molecular tools, computer software and sophisticated laser microscopy techniques which we've been developing at McMaster over the last seven years, researchers can now use these methods to hopefully watch a drug stop this from happening."

Truant's laboratory is supported by grants from the United States High Q Foundation, the Canadian Institutes of Health Research, the Huntington Society of Canada and the Canada Foundation for Innovation.

"This discovery reflects Dr. Truant's growing contribution to the international campaign to create a world free from Huntington disease," says Don Lamont, CEO & Executive Director of the Huntington Society of Canada — Canada's only organization focused on research, education and support in the HD field.

"Our families live on a 'tightrope' waiting for an effective treatment or a cure for HD", says Lamont. "The discovery provides hope for the Huntington community — most of all, hope that their children will not have to suffer the devastation of this inherited disease."

An international team of researchers has published a benchmark study showing that gene expression in several animal models of Huntington's Disease (HD) closely resembles that of human HD patients.

The results, published August 1, 2007, in the journal Human Molecular Genetics, validate the applicability of using animal models to study human disease and will have important consequences for the pertinence of these models in preclinical drug testing.

Huntington's disease is an incurable and fatal hereditary neurodegenerative disorder caused by a mutation in the gene that encodes the huntingtin protein. Neurons in certain regions of the brain succumb to the effects of the altered protein, leading to severe motor, psychiatric, and cognitive decline. Several recent studies have shown that the mutant huntingtin protein modifies the transcriptional activity of genes in affected neurons. This disease mechanism is a promising new avenue for research into the causes of neuronal death and a novel potential approach for treatment.

Led by EPFL professor Ruth Luthi-Carter, and involving collaborators from six countries, the current study found a marked resemblance between the molecular etiology of neurons in animal models and neurons in patients with HD. This implies that animal models are relevant for studying human HD and testing potential treatments.

To come to this conclusion, the scientists measured the gene expression profile of seven different transgenic mouse models of HD, representing different conditions and disease stages. These profiles clarified the role of different forms and dosages of the protein hungtintin in the transcriptional activity of neurons.

They then designed and implemented novel computational methods for quantifying similarities between RNA profiles that would allow for comparisons between the gene expression in mice and in human patients. "Interestingly, results of different testing strategies converged to show that several available models accurately recapitulate the molecular changes observed in human HD," explains Luthi-Carter. "It underlines the suitability of these animal models for preclinical testing of drugs that affect gene transcription in Huntington's Disease."

A drug used in some countries to treat the symptoms of Huntington's disease prevents death of brain cells in mice genetically engineered to mimic the hereditary condition, UT Southwestern Medical Center researchers have found.

The research sheds light on the biochemical mechanisms involved in the disease and suggests new avenues of study for preventing brain-cell death in at-risk people before symptoms appear.

"The drug can actually prevent brain cells from dying," said Dr. Ilya Bezprozvanny, associate professor of physiology at UT Southwestern. "It's much more important than people thought."

The study, of which Dr. Bezprozvanny is senior author, appears in the July 25 issue of The Journal of Neuroscience.

The drug, called tetrabenazine (TBZ), is commercially distributed as Xenazine or Nitoman and blocks the action of dopamine, a compound that some nerve cells use to signal others. TBZ is approved for use in several countries, but not the U.S., to treat uncontrollable muscle movements in Huntington's and other neurological conditions.

Huntington's is a fatal genetic condition that usually manifests around ages 30 to 45, according to the Huntington's Disease Society of America. About one in 10,000 people in America have the disease, with another 200,000 at risk. One of the most famous people with Huntington's was folk singer Woody Guthrie, who died in 1967.

Huntington's is caused by a dominant gene, meaning that a person carrying the gene is certain to develop the disease and has a 50 percent chance of passing it on to his or her children. Symptoms include jerky, uncontrollable movements called chorea and deterioration of reasoning abilities and personality. Symptoms begin after many brain cells have already died.

Although a genetic test exists, some people with a family history of Huntington's choose not to be tested because there is no cure and because they fear loss of health insurance. There are treatments to lessen the symptoms, but there is currently no way to slow or halt the progression of the disease.

In the current study, the UT Southwestern researchers used mice that were genetically engineered to carry the mutant human gene for Huntington's, causing symptoms and death of brain cells similar to those seen in the disease. The study focused on an area of the brain called the striatum, which plays a critical role in relaying signals concerning motion and higher thought and receives signals from several brain regions.

The striatum is primarily made up of nerve cells called medium spiny neurons, which undergo widespread death in Huntington's. One major input to the striatum comes from an area called the substantia nigra, which controls voluntary movements and sends signals to the striatum via nerve cells that release dopamine.

The researchers conducted various coordination tests on both normal and genetically manipulated mice. Engineered mice given a drug that increased brain dopamine levels performed worse on these tasks, while TBZ protected against this effect. Most importantly, TBZ appears to reduce significantly cell loss in the striatum of the engineered mice, the scientists report.

"More research is needed to determine whether this protective effect might also be present in humans, and also whether at-risk people would benefit from the drug," Dr. Bezprozvanny said.

Clinical trials in humans would be very difficult, however, because trials require many participants and there is no easy way to score effectiveness of a presymptomatic drug, Dr. Bezprozvanny said. Thus, his future studies in animals will look at the effectiveness of TBZ given just after initial symptoms have developed. This situation simulates what would probably happen in a human trial, he said.

Other UT Southwestern researchers involved in the study were Dr. Tie-Shan Tang, instructor in physiology; and Dr. Xi Chen and Dr. Jing Liu, postdoctoral researchers in physiology.

The work was supported by the Robert A. Welch Foundation, the Huntington's Disease Society of America, the Hereditary Disease Foundation, the HighQ Foundation and the National Institute of Neurological Disorders and Stroke.