Huntington’s disease is an inherited condition which is usually first noticed in patients after the age of 30 when damage to the nerve cells in parts of the brain causes increasing behavioural and physical symptoms. What starts with forgetfulness and small tremors can deteriorate to involuntary jerking, rapid weight loss, deep depressions and violent outbursts over years or decades. The research by Leeds University with scientists in Milan, America and King’s College London, looked at the molecular pathways in the brain of people with Huntington’s and found that the protein that wreaks havoc in their nerve cells is responsible for knock-on effects in 57 separate genes. The findings suggest that this is why the disease has such wide-ranging and catastrophic emotional and physical symptoms.

Scientists have now begun the painstaking work of matching the defective genes to some of the disease’s symptoms. “This is a really exciting breakthrough,” said researcher 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 clinical trials should speed up the time for this research to impact directly on patients.

“This is the first step to identifying the molecular pathways which may be important in Huntington’s. This will help us develop other treatments. It’s early stages but it could be incredibly important and offers an explanation as to why the symptoms of this disease are so broad.”

The drug that they are most interested in is called Trichostatin C, and scientists are working on it to analyse its effects for a number of cancers. But the drug is so wide ranging that there have been concerns about serious side effects. The symptoms of Huntington’s can be managed through medication, but there is no definitive treatment. This research provides a first step in developing a treatment that may even halt the onset of the disease, researchers said.

Cath Stanley, head of care services at the Huntington’s Disease Association, said: “It 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 [until] their symptoms start to develop.”

The research was published in the Journal of Neuroscience.

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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 - making the drug more important than people originally thought.

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 is still awaiting FDA approval in the US. It is used to treat uncontrollable muscle movements in Huntington’s and other neurological conditions.

In the 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.
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.

For further (important) information, please read this page by Dr. LaVonne Veatch Goodman at the HD Drug Works site.

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Working with American researchers they developed man-made compounds capable of blocking a nerve cell interaction known to lead to the symptoms of the disease. The results of the study - carried out in the laboratory using a model of the disease - have prompted the Alzheimer’s Research Trust to help fund a further three years research.

A drug that can stop Alzheimer’s disease from killing brain cells is a holy grail for researchers working to overcome the devastating condition which affects more than 500,000 people in the UK alone. The number of sufferers is expected to double to more than one million with the general ageing of the population over the next generation.

Alzheimer’s is linked to the build-up of amyloid protein, which eventually forms “senile plaques”. The amyloid protein inflicts damage by interacting with an enzyme called amyloid beta alcohol dehydrogenase (ABAD) and releasing toxic substances which kill brain cells.

Researchers at St Andrews University initially focused on developing the three-dimensional shape of ABAD and understanding how amyloid attaches itself to the structure.

Dr Frank Gunn-Moore, senior lecturer at the university’s school of biology, said: “Alzheimer’s sufferers produce too much amyloid and ABAD in their brains. Based on our knowledge of ABAD, we produced an inhibitor that can prevent amyloid attaching to it in a living model.”

Dr Gunn-Moore, who led the research, added: “We have shown that it is possible to reverse some of the signs associated with Alzheimer’s disease. The work is now being continued to try and refine the inhibitor into a potential drug. Our research holds a possible key for the treatment of Alzheimer’s disease, particularly in its early stages.”

Dr Susanne Sorensen, head of research with the Alzheimer’s Society, said: “The study provides another important piece in the puzzle for understanding Alzheimer’s disease and points toward a possible new treatment target, which has so far been unexplored.”

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The research builds on a chance discovery that U-M microbiologist Matthew Chapman and co-workers made five years ago. In research initially aimed at understanding urinary tract infections, they discovered that the common bacterium Escherichia coli makes and employs amyloid fibers, the same types of fibers that are the calling cards of many neurodegenerative diseases. Until then, amyloids were considered “biological blunders” that occurred only when proteins misfolded into deviant forms that aggregate into harmful clumps, Chapman said. But his work showed that bacteria produce amyloid fibers “by design” and use them to adhere to surfaces and to interact with other bacteria.

You can read the full article on ScienceDaily.

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In an upcoming issue of the journal Science, the investigators describe finding, in cellular and animal models, that blocking the action of an enzyme called SIRT2 can protect the neurons damaged in Parkinson’s disease from the toxic effects of alpha-synuclein, a protein that accumulates in the brains of Parkinson’s patients. The study, which also suggests that inhibiting this pathway could help in the treatment of other conditions in which abnormal proteins accumulate in the brain, is receiving early online release on the Science Express website at http://www.sciencexpress.org.

The researchers plan to study the effect of the new inhibitor AGK2 in models of HD.

The full press release, along with editorial comments, can be found on the HD Lighthouse website.

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Dr. Goodman believes the real and practical “take home” message from this important study is that HD people may now have two good reasons to take Creatine.

Read the full article on the HD Drug Works site.

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Researchers at the University of Cambridge found that daily treatments of Alprazolam or chloral hydrate, two different sedative drugs, enabled them to develop a regular sleep pattern and improved their cognitive function – their ability to understand and act on information.

According to the Cambridge neuroscientists conducting the research, HD mice have abnormal circadian rhythms; their daily sleeping and waking cycles are disrupted and irregular. Since sleep disruption contributes to problems with perception and learning in healthy people, the team wondered whether the circadian disruption and cognitive disturbances in HD mice were linked.

To test this, drugs were administered to regulate sleep patterns in the mice. The results, published in the current issue of the Journal of Neuroscience, show that both drugs caused a noticeable improvement in learning and Alprazolam also improved arousal. The study shows for the first time that treatments aimed at restoring normal sleep-wake activity could slow the cognitive decline that is such a devastating feature of the disease.

Dr. Jenny Morton, lead author of the study, said: “In the future, more attention should be paid to understanding sleep and circadian disturbance in HD. Management of these patterns may not only improve patients ability to think, learn and perform, but would also improve quality of life for both them and their carers.”

The results have short-and long-term implications for treatment of HD and for the reversal of the disease’s impairments. Recognising that sleep disturbance is a part of the disease means that clinicians should include focused management of sleep symptoms in their treatment of HD patients.

Taken from a press release by the University of Cambridge. Based on an article by Patrick N. Pallier et al, and originally published by The Journal of Neuroscience [July 18, 2007]. Photo by Kris Krug.

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