Category: Huntington’s Disease

A cure for debilitating genetic diseases such as Huntington's disease, Friedreich's ataxia and Fragile X syndrome is a step closer, thanks to a recent finding in plant DNA that has similarities to certain genetic abnormalities in humans.

The finding, which was published in Science on January 15, is the result of a collaboration between a team led by Dr Sureshkumar Balasubramanian at The University of Queensland's School of Biological Sciences and Professor Dr Detlef Weigel at the Max Planck Institute for Developmental Biology in Germany.

It identifies an expansion of a repeat pattern in the DNA of the plant Arabidopsis thaliana that has striking parallels to the DNA repeat patterns observed in humans suffering from neuronal disorders such as Huntington's disease and Fredereich's ataxia.

Lead researcher from UQ, Dr Balasubramanian, said being able to use the plant as a model would pave the way toward better understanding of how these patterns change over multiple generations.

"It opens up a whole new array of possibilities for future research, some of which could have potential implications for humans," Dr Balasubramanian said.

The types of diseases the research relates to, which are caused by "triplet repeat expansions" in DNA, become more severe through the generations but were difficult to study in humans due to the long timeframes involved.

A plant model with a relatively short lifespan would allow scientists to study DNA mutations over several generations, Dr Balasubramanian said.

The study also had implications beyond human diseases, Dr Balasubramanian said.

While the DNA patterns were previously only seen in humans, current findings have shown the patterns occur in in distant species such as plants, providing new scope for researchers in all disciplines of biology.

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Journal Reference:

1. Sridevi Sureshkumar, Marco Todesco, Korbinian Schneeberger, Ramya Harilal, Sureshkumar Balasubramanian, and Detlef Weigel. A Genetic Defect Caused by a Triplet Repeat Expansion in Arabidopsis thaliana. Science, 2009; DOI: 10.1126/science.1164014

Researchers at the Yerkes National Primate Research Center, Emory University, have discovered dental pulp stem cells can stimulate growth and generation of several types of neural cells. Findings from this study, available in the October issue of the journal Stem Cells, suggest dental pulp stem cells show promise for use in cell therapy and regenerative medicine, particularly therapies associated with the central nervous system.

Dental stem cells are adult stem cells, one of the two major divisions of stem cell research. Adult stem cells have the ability to regenerate many different types of cells, promising great therapeutic potential, especially for diseases such as Huntington’s and Parkinson’s. Already, dental pulp stem cells have been used for regeneration of dental and craniofacial cells.

Yerkes researcher Anthony Chan, DVM, PhD, and his team of researchers placed dental pulp stem cells from the tooth of a rhesus macaque into the hippocampal areas of mice. The dental pulp stem cells stimulated growth of new neural cells, and many of these formed neurons. “By showing dental pulp stem cells are capable of stimulating growth of neurons, our study demonstrates the specific therapeutic potential of dental pulp stem cells and the broader potential for adult stem cells,” says Chan, who also is assistant professor of human genetics in Emory School of Medicine.

Because dental pulp stem cells can be isolated from anyone at any age during a visit to the dentist, Chan is interested in the possibility of dental pulp stem cell banking. “Being able to use your own stem cells for therapy would greatly decrease the risk of cell rejection that we now experience in transplant medicine,” says Chan.

Chan and his research team next plan to determine if dental pulp stem cells from monkeys with Huntington’s disease can enhance brain cell development in the same way dental pulp stem cells from healthy monkeys do.

 An over-the-counter vitamin in high doses prevented memory loss in mice with Alzheimer's disease, and UC Irvine scientists now are conducting a clinical trial to determine its effect in humans.

Nicotinamide, a form of vitamin B3, lowered levels of a protein called phosphorylated tau that leads to the development of tangles, one of two brain lesions associated with Alzheimer's disease. The vitamin also strengthened scaffolding along which information travels in brain cells, helping to keep neurons alive and further preventing symptoms in mice genetically wired to develop Alzheimer's.

"Nicotinamide has a very robust effect on neurons," said Kim Green, UCI scientist and lead author of the study. "Nicotinamide prevents loss of cognition in mice with Alzheimer's disease, and the beauty of it is we already are moving forward with a clinical trial."

The study appears online Nov. 5 in the Journal of Neuroscience.

Nicotinamide is a water-soluble vitamin sold in health food stores. It generally is safe but can be toxic in very high doses. Clinical trials have shown it benefits people with diabetes complications and has anti-inflammatory properties that may help people with skin conditions.

Nicotinamide belongs to a class of compounds called HDAC inhibitors, which have been shown to protect the central nervous system in rodent models of Parkinson's and Huntington's diseases and amyotrophic lateral sclerosis. Clinical trials are underway to learn whether HDAC inhibitors help ALS and Huntington's patients.

In the nicotinamide study, Green and his colleague, Frank LaFerla, added the vitamin to drinking water fed to mice. They tested the rodents' short-term and long-term memory over time using water-maze and object-recognition tasks and found that treated Alzheimer's mice performed at the same level as normal mice, while untreated Alzheimer's mice experienced memory loss.

The nicotinamide, in fact, slightly enhanced cognitive abilities in normal mice. "This suggests that not only is it good for Alzheimer's disease, but if normal people take it, some aspects of their memory might improve," said LaFerla, UCI neurobiology and behavior professor.

Scientists also found that the nicotinamide-treated animals had dramatically lower levels of the tau protein that leads to the Alzheimer's tangle lesion. The vitamin did not affect levels of the protein beta amyloid, which clumps in the brain to form plaques, the second type of Alzheimer's lesion.

Nicotinamide, they found, led to an increase in proteins that strengthen microtubules, the scaffolding within brain cells along which information travels. When this scaffolding breaks down, the brain cells can die. Neuronal death leads to dementia experienced by Alzheimer's patients.

"Microtubules are like highways inside cells. What we're doing with nicotinamide is making a wider, more stable highway," Green said. "In Alzheimer's disease, this highway breaks down. We are preventing that from happening."

Duke University Medical Center scientists have made a significant finding that could lead to better drugs for several degenerative diseases including Huntington's disease and Alzheimer's disease.

Compounds that block the activity of a specific enzyme prevented brain injury and greatly improved survival in fruit flies that had the same disease process found in Huntington's disease.

"We were able to prevent Huntington's disease-like illness in mutant fruit flies by giving them orally active transglutaminase inhibitors," said Charles S. Greenberg, M.D., a Professor of Medicine and Pathology at Duke University Medical Center and senior author of the paper. The drug blocks the action of an enzyme called tissue transglutaminase (TGM2). TGM2 may damage cells by forming strong bonds between proteins. Such bonding is beneficial for blood clotting which happens outside of cells, but if this type of bonding occurs inside cells, it can be harmful, Greenberg said.

The study appears in the current issue of Chemistry and Biology.

Huntington's disease causes uncontrolled movement and mental deterioration that develops later in life, and though there is no cure, people can get tested to learn whether they have the gene that causes the devastating illness, Greenberg said.

Alzheimer's disease, Parkinson's disease and polyglutamine diseases including Huntington's disease may possibly be improved with the same compounds, said Thung S. Lai, Ph.D., lead author and a Duke Associate Professor of Medicine. "Our findings may also help to develop drugs that block the pathology related to transglutaminase's action. That action has been linked to the development of tissue fibrosis, organ failure and aging."

While these compounds were promising in the animal system, they are several years away from entering any human trials, Greenberg said. "We will be studying these compounds in diseases in which TGM2 produces tissue injury."

For the study, Lai painstakingly screened 2,000 compounds. Only two groups of drugs were found to be effective TGM2 inhibitors. Some of the most potent TGM2 inhibitors were given to the fruit flies along with their food.

The most effective compound was a kinase inhibitor, a drug that had been developed several years ago for another purpose. The other beneficial compounds fell into a category of drugs that attack a sulfhydryl group in a protein.

The next step is to use the effective compounds as the backbone for developing even more effective drugs, Lai said. The scientists plan to test whether the TGM2 inhibitors they identified would prevent the fibrous tissue process that causes chronic renal, vascular and lung disease.

The work was funded in part by National Institutes of Health grants. This study required extensive teamwork between several departments at Duke and a long-time collaborator at Wake Forest University.

Other authors on the paper include Yusha Liu, Tim Tucker, James R. Burke and Warren J. Strittmatter of the Duke Department of Medicine; Kurt R. Daniel and David C. Sane of the Department of Internal Medicine-Cardiology, Wake Forest University School of Medicine in Winston-Salem, N.C.; and Eric Toone of the Duke Department of Chemistry.

The damage to brain tissue seen in Huntington's disease may be caused by an overactive immune response in the bloodstream and the brain, according to new findings from two teams of researchers at the University of Washington in Seattle and University College London. The findings will be published online July 14 in the Journal of Experimental Medicine.

Working separately, the two teams found evidence in both brain cells and the bloodstream suggesting an important link between the immune system's response and Huntington's disease. Together, the findings may help scientists find biological markers for monitoring the disease progression earlier and with more accuracy, and could help them develop new treatments for the disease. Huntington's is a fatal inherited neurodegenerative disorder for which there is currently no effective treatment.

The UW team, lead by Dr. Thomas Moeller, research associate professor of neurology, had previously studied the role of inflammation and immune response in neurodegenerative diseases like Huntington's and ALS, also known as Lou Gehrig's disease. In this study, they found that patients with Huntington's had higher levels of immune-system signaling molecules, called cytokines, in their brain tissue.

The UW researchers then looked at a mouse-based model of the disease, studying the response of microglia, the immune cells of the nervous system. When the microglia were treated with a molecule triggering an immune response, the microglia from Huntington's mice produced much higher levels of cytokines, the immune system molecules. That finding suggests that the protein produced by the Huntington's disease genetic mutation, a protein called huntingtin, is causing the immune cells to be overactive. The researchers think that overly strong immune response may be the mechanism through which the disease causes damage to neurons in the brain.

"When we found increased levels of cytokines in the brains of Huntington's disease patients, we were very excited," Moeller said. "Inflammation in the brain has been increasingly recognized as an important component in other neurodegenerative diseases such as Alzheimer's or Parkinson's disease. These findings might open the door to novel therapeutic approaches for Huntington's disease that target inflammation."

The team at University College London focused their work on immune cells in the bloodstream, and found similar results linking the disease to the body's immune response.

"The similar effect in the blood of Huntington's patients suggests that we have discovered a new pathway in the disease by which the mutant protein could cause damage," Moeller explained. "The protein could be causing damage through an abnormally overactive immune system in both the blood and the brain. While damage from Huntington's is typically seen in the brain, this new pathway is quite easy to detect in the blood of patients, so we may have found a unique window from the blood into what the disease is doing in the brain."

The immune response in the blood may also help researchers use immune-system molecules as biological markers for the disease, which can be difficult to diagnose in early stages. Better tracking of Huntington's disease progression may help researchers to fine-tune interventions aimed at slowing the disease before it has affected as much brain tissue.

Huntington's affects an estimated 30,000 people in the United States. It is characterized by loss of motor control and cognitive functions, as well as by depression or other psychiatric problems.

Both the UW and University College London research projects were supported by CHDI, Inc., a nonprofit organization that provides funding for Huntington's disease research.

Research using newly developed Magnetic Resonance Imaging technology could soon allow clinicians to confirm Huntington's disease before symptoms appear in people who have the gene for the fatal brain disease.

An early confirmation of Huntington's disease in people who have tested gene positive for the disease could enable treatment to commence early, even before motor, cognitive and psychiatric symptoms arise.

Using Diffusion Magnetic Resonance Imaging (dMR), researchers from the Howard Florey Institute and Monash University in Melbourne have identified extensive white matter degeneration in patients recently diagnosed with Huntington's disease.

White matter forms the connections between brain regions, allowing one region to communicate with another. A breakdown of these structural connections in the brain could help to explain the complex motor and cognitive problems experienced by Huntington's disease patients in the early stages of the disease.

Scientists have recently shown that this white matter degeneration starts before patients are officially diagnosed however, the extent of white matter degeneration in Huntington's disease was previously unknown.

The early symptoms of Huntington's disease can be easily missed, as they are usually minor problems such as clumsiness, memory loss and loss of cognitive function.

These symptoms gradually become more severe over the years, inevitably leading to death within 15 to 20 years of diagnosis.

Working on this research was Florey PhD student Ms India Bohanna, who said this discovery could also assist in the future testing of new therapeutic strategies to treat the disease.

"Currently, the effectiveness of any new treatment is determined by its ability to reduce symptoms, but we know that changes in the brain occur a long time before symptoms arise," Ms Bohanna said

"Our discovery could allow researchers to test therapies even before symptoms appear.

"Not only does this research tell us more about how the brain degenerates early in Huntington's disease, but it also opens up new avenues in drug research and development.

Co-principal investigator, A/Prof Nellie Georgiou-Karistianis from Monash University explained, "By using diffusion MR to examine white matter degeneration early on, we can now test the ability of new therapeutics that may possibly reverse underlying degeneration in brain connections, which ultimately leads to the development of symptoms.

"Although there isn't yet a cure for Huntington's, researchers at the Florey and Monash, and from around the world are working to develop new treatments to delay the onset and severity of this devastating disease," A/Prof Georgiou-Karistianis said.

Collaborating on this project was the Florey's A/Prof Anthony Hannan, who has shown that mental and physical exercise can delay the onset of Huntington's disease and slow the progression of symptoms in a mouse model of the disease.

This is the first study to look at white matter changes across the whole brain in Huntington's disease, and importantly, to study how the breakdown of connections between brain regions might lead to the widespread deficits found in Huntington's disease patients.

The researchers hope to conduct further dMR studies to examine white matter degeneration in people who have tested gene positive to Huntington's disease but are up to 10 years away from developing symptoms.

Huntington's disease is an inherited disease caused by a mutation in a single gene and is inherited by 50 percent of the offspring of patients. The disease usually appears around middle age but can start in childhood. Huntington's disease affects approximately 7 people per 100,000 of the population in Australia.

Diffusion Magnetic Resonance Imaging is a recently developed brain imaging technique that enables examination of the brain at a microstructural level and the mapping of white matter tracts by tracking the movement of water in the brain.

This research will be presented at the 14th Annual Meeting of the Organisation for Human Brain Mapping, which opened on 15 June in Melbourne.

This research has also been accepted for publication in Brain Research Reviews.

Scientists have developed the first genetically altered monkey model that replicates some symptoms observed in patients with Huntington's disease, according to a new study funded by the National Institutes of Health. Researchers are now able to better understand this complex, devastating and incurable genetic disorder affecting the brain. This advance, reported in the May 18 advance of online publication edition of Nature, could lead to major breakthroughs in the effort to develop new treatments for a range of neurological diseases.

Huntington's is an inherited disease caused by a defective gene that triggers certain nerve cells in the brain to die. Symptoms may include uncontrolled movements, mood swings, cognitive decline, balance problems, and eventually losing the ability to walk, talk or swallow. It affects five to 10 people in every 100,000. There is no known treatment to halt progression of the disease, only medications to relieve symptoms. Death typically occurs 15 to 20 years after onset.

This study marks the first time that researchers have developed a rhesus macaque model of a specific human disease using transgenic technologies, a marked improvement over mouse models. Transgenic animals are created using a recombinant DNA method to modify a genome.

"This research allows scientists to advance beyond mouse models which do not replicate all of the changes in the brain and behavior that humans with Huntington's disease experience," said John D. Harding, Ph.D., director of primate resources at the NIH's National Center for Research Resources (NCRR), which funded the study. "Primate models better mirror human diseases and are a critical link between research with small laboratory animals and studies involving humans."

To unravel the genetic components of this disease, NIH-supported researchers Anthony W.S. Chan, D.V.M., Ph.D.; Xiao-Jiang Li, M.D., Ph.D.; and Shi-Hua Li, M.D., Ph.D., collaborated with their colleagues at the Yerkes National Primate Research Center and other components of Emory University in Atlanta. The research was supported by the NCRR and the National Institute of Neurological Disorders and Stroke (NINDS) at NIH.

The Emory research team developed this transgenic monkey model by introducing altered forms of the Huntington gene into monkey eggs using a viral vector. The eggs were fertilized and the resulting embryos were introduced into surrogate mothers, resulting in five live births. The investigators are now studying the onset of the disease and its behavioral and cognitive effects, with the goal of using the monkey model to better understand disease mechanisms and to design therapies.

Chan, an assistant research professor at the Yerkes Research Center and an assistant professor in the Department of Human Genetics, and his research team  produced the HD transgenic rhesus macaques by:

Injecting130 mature oocytes with:

• a lentivirus expressing the mutant htt gene with expanded polyglutamine repeats, which is the primary cause of HD, and
• a lentivirus expressing a green fluorescent protein (GFP) gene;

Fertilizing the oocytes by intracytoplasmic sperm injection (ICSI); and

• Transferring 30 embryos into eight surrogates.
• This resulted in six pregnancies and five live births (two sets of twins and one singleton); all carried the mutant htt and GFP genes. Two continue to survive.

"Genetic advances make it easy to identify who has inherited the disease gene," said Walter Koroshetz, M.D., deputy director of the NINDS. "Now, with a primate model of Huntington's disease, we are one large step closer to finding better treatments for people with the disease as well as those destined to develop it."

The Yerkes primate center where this advance was made is one of eight supported by NCRR. The centers provide leadership, training and resources to foster scientific discovery and compassionate, quality animal care. Last year, the eight centers located around the country supported more than 2,000 researchers studying a wide range of diseases using non human primate models.

"Yerkes primate center is an ideal place to carry out this work because of its expertise in nonhuman primate transgenesis, non-invasive neural imaging, and experience with behavior assessment," said Dr. Harding.

The simple act of running in an exercise wheel delays the onset of some symptoms of Huntington's disease in a mouse model of the fatal human disorder according to new research. These findings add insights into the pathogenesis of the disease and suggest possible preventive therapeutic targets.

Huntington's disease affects up to one person in every 10 000, but clusters in families and certain populations. Affected people develop clusters of a defective protein in their neurons and shrinkage of brain areas associated with movement. The disorder causes disability and eventually death, but does not normally manifest until after people have had children, allowing the disease gene to be passed on.

"Although Huntington's disease is considered the epitome of genetic determinism, environmental factors are increasingly recognised to influence the disease progress", the researchers write.

The research team from the University of Oxford and the Howard Florey Institute, University of Melbourne, report findings of a study in mice with the genetic mutation that causes Huntington's in humans. Just as mentally stimulating these mice by enriching their environment had previously been shown to delay onset and progression of motor symptoms, so does the simple physical activity of running in a wheel.

"Of particular interest was the fact that the wheel exercise was started in juvenile mice, much earlier than in a previous study that showed more limited protective effects of physical activity," explains Anthony Hannan of the Howard Florey Institute. This finding suggests that the protective effect has a specific time window.

Hannan notes "Physical activity did not postpone all the motor symptoms delayed by environmental enrichment, which suggests that sensory stimulation, mental exercise, and physical activity could all be used for the benefit of human sufferers". Early intervention is also possible in people who will develop Huntington's, because genetic diagnosis is possible.

Density of protein aggregates in neurons and shrinkage in brain regions in mice that had benefited from physical activity were as advanced as in those raised without wheels, the authors suggest therefore that benefits stem from stimulation of neuronal receptors and other molecules that prolongs normal function and delays motor deficits.

Journal reference: Wheel running from a juvenile age delays onset of specific motor deficits but does not alter protein aggregate density in a mouse model of Huntington's disease. Anton van Dellen, Patricia M Cordery, Tara L Spires, Colin Blakemore and Anthony J Hannan. BMC Neuroscience (in press)

Researchers at the University of Warwick and the Indian Institute of Technology Kanpur have discovered that the mechanism that we rely on to transport iron safely through our blood stream can, in certain circumstances, collapse into a state which grows long worm-like "fibrils" banded by lines of iron rust. This process could provide the first insight into how iron gets deposited in the brain to cause some forms of Parkinson's & Alzheimer's and Huntington's diseases.

Human blood relies on a protein called transferrin to safely transport iron through the bloodstream to points were it can be usefully and safely used in the body. In most other circumstances exposed iron contains many dangers for human cells. When deposited in such a state in the brain it can play a role in neurodegenerative diseases such as Parkinson's, Huntington's and Alzheimer's

Transferrin takes up iron out of bloodstream and transports it by a method that combines it with carbonate to bind to two sites on the surface of the transferrin protein. It then curls around the iron and seals it in, almost like a Venus flytrap plant, to prevent it from interacting with anything else until it reaches where it is needed and can safely be used.

The research team led by Professor Peter Sadler from the University of Warwick, and Professor Sandeep Verma from the Indian Institute of Technology, found that if they took transferrin and left it to dry out on a surface, molecules of the safe transporter of iron assembled themselves into tendril – or worm-like fibrils.

Even more interestingly the iron that was once safely wrapped up inside the transferrin now appeared to be settling along the length of these fibrils plating them in a series of spots or bands along the length of the tendril shape. This leaves the iron dangerously exposed and available to interact in ways that could cause cell damage.

Deposits of iron exposed in this way and found in the brain are a possible cause of some forms of Parkinson's, Alzheimer's and Huntington's diseases. Until now there has been no real idea as to how iron becomes deposited there in such a dangerous way. As it is essential for the brain to have iron safely delivered to it, this observation could provide the first real clue as to how that iron comes to be deposited there in such a dangerous way. The research chemists who led this study hope that neurology researchers will be able to build on this work to gain more understanding of how these forms of Parkinson's, Huntington's and Alzheimer's occur and how they can be countered.

The full research paper entitled Periodic Iron Nanomineralization in Human Serum Transferrin Fibrils, by Surajit Ghosh, Arindam Mukherjee, Peter J. Sadler, Sandeep Verma, has just been published in the online edition of Angewandte Chemie. The lead authors are Professor Peter Sadler from the University of Warwick, and Professor Sandeep Verma from the Indian Institute of Technology.

Hoping to piece together the intricate series of interactions that lead to Huntington's disease, Indiana University Bloomington scientists have determined the shape and structure of a binding site that may prove useful in combating the neurodegenerative disease.

In the Feb. 1 issue of Journal of Molecular Biology, IU Bloomington biologists Joel Ybe and Qian Niu describe a region on the surface of HIP1 (Huntingtin-interacting protein 1) that could bind HIPPI (HIP1-protein interactor). The association of HIP1 and HIPPI is believed to lead to the degeneration of nerve cells.

"If we now think that this is the region where HIPPI binds, we could eventually design a drug that can come in and sit down between these two proteins, which would prevent the binding of HIPPI," said Ybe, who led the research.

Ybe and Niu's paper is the first to scrutinize a Huntington's disease-related protein's structure and function at the molecular level. Ybe and colleagues hope meticulous study of each Huntington's disease protein will suggest new avenues for wholesale prevention.

"The important thing for us is to come up with something that will potentially help people," said Ybe. "What is happening before the manifestation of the disease? Can we use this information to come up with drugs to diffuse that process?"

Huntington's disease is a hereditary disorder that causes large numbers of nerve cells to die. About 30,000 people in the U.S. are estimated to have the disease — approximately one person in ten thousand. Symptoms include uncontrolled movements, dementia and depression, but these symptoms do not usually appear until the afflicted reach their 30s or 40s. Despite major strides forward in understanding the disease in recent years, there is currently no cure.

The disease begins when the huntingtin protein falls off HIP1. The vacancy allows another protein, HIPPI, to then bind to HIP1. The complex of HIP1 and HIPPI is responsible for activating other proteins that cause the death of cells. The loss of large amounts of nerve cells leads to a loss of motor function, and eventually brain function, too.

Ybe and Niu used X-ray crystallography to look at an area of interest on the surface of HIP1, which works in concert with clathrin to traffic nutrients into a cell, and has long been implicated as playing an important role in the development of Huntington's disease. They learned that the potential binding surface of HIPPI in HIP1 has an unexpected shape for a binding site, a spiraling spiral called a "coiled coil." This finding was contrary to predicted results that the binding surface that receives HIPPI is folded into a so-called death effector domain.

Using the information from the published molecular structure of HIP1, IU biologists hope to be able to test which protein connections are ultimately responsible for triggering the chain of interactions leading to Huntington's disease and how to block them. For example, they observed that clathrin, protein involved in bringing nutrients to the cell, binds with HIP1 right next door to where HIPPI binds. While clathrin "packages" nutrients for a cell, HIP1 connects these "baskets" to the structure of the cell. If HIPPI binding with HIP1 prevents clathrin connection with HIP1, then the normal pathway of nutrients into a cell is interrupted, causing changes in the cells ability to function normally.

"Until we understand the relationship between huntingtin protein, HIP1, clathrin and HIPPI — we are not going to understand what is happening in the person who has the disease," says Ybe. "You understand what's going on in healthy cells, before you understand what's going on in diseased cells."

The research was funded by the National Institutes of Health and the Ybe laboratory has recently been awarded a discovery grant from the High Q Foundation to support future work. Ybe first presented results from this work at the World Congress on Huntington's Disease in Dresden, Germany, last year.