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Huntington’s Disease Protein Affects Nerve Signaling; Study Suggests New Treatments

For release: Thursday, June 26, 2008

The abnormal protein found in Huntington’s disease (HD) leads to an unusually large amount of nerve signaling early in the disease process, before other problems appear, a new study shows.  Partially blocking these nerve signals prevents neuron death and loss of motor function in fruit flies models of HD.  The findings suggest possible new ways of delaying the onset or slowing the progression of the disease.

Since the gene mutation that causes HD was identified in 1993, researchers have been trying to learn how it triggers the disease.  HD affects an estimated 30,000 people in the United States and causes symptoms such as loss of coordination and balance, uncontrolled movements, muscular contractions, mood changes, and memory problems.  There is currently no treatment that can stop the progression of the disorder.

"We need to look for alternative approaches to treat incurable diseases," says Juan Botas, Ph.D., of Baylor College of Medicine in Houston, who led the new study.  Dr. Botas and his colleagues decided to investigate how the abnormal, expanded version of the gene that causes HD affects neural function in fruit flies in order to learn more about how the disease develops and how it might be treated.  The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the journal Neuron.[1]

Previous studies have shown that cells break the abnormal protein produced by the HD gene mutation into fragments. These fragments accumulate in clumps within neurons and disrupt cell function in a number of ways, including changing the function of synapses — the gaps between neurons where nerve signaling chemicals (neurotransmitters) are released.  Other changes, including disruptions of gene activity and impaired functioning of nerve fibers and mitochondria (energy-producing structures within cells), also may affect nerve signaling in HD.  However, whether the changes in nerve signaling are part of the cause of the disease or if they are a result has not been clear.

Most studies in models of HD have used animals that have only a fragment of the abnormal protein (called htt), instead of the whole protein. Such models do not have the same pattern of neurodegeneration as animals with the entire protein.  To avoid this problem, Dr. Botas and his colleagues developed flies with the full-length abnormal protein for their study.

Flies with the full-length abnormal htt protein showed progressive loss of neurons and had shorter lifespans than other flies, the researchers found.  The affected flies had an impaired ability to climb and fly.  The study also showed that the abnormal protein triggered an unusually high transmission of nerve signals between neurons. 

The researchers then developed flies that had the abnormal htt gene along with a partial loss of calcium channel genes or other genes needed for normal synaptic function. The absence of the channel genes reduced synaptic function and counteracted the excessive nerve signaling in the flies.  As a result, the flies maintained normal amounts of nerve signaling, despite the presence of the abnormal htt protein.  Moreover, they did not develop neuron loss or movement problems.

The abnormal nerve signaling developed in the flies before htt protein fragments accumulated in the cells' nuclei, Dr. Botas and his colleagues found.  The fact that the aberrant nerve signaling develops at a very early stage in the disease process suggests that reducing this abnormal activity in people with the htt gene mutation might delay the onset of HD or slow progression of the disease.  Researchers have found a number of drugs that reduce nerve signaling, including calcium channel blockers, which are widely used to treat high blood pressure in people. 

Since the abnormal neurotransmission found in this study does not affect the accumulation of htt fragments in the cell, reducing the aberrant cell signaling is unlikely to completely cure HD.  However, it might reduce or delay the effects of the disease, Dr. Botas says.  "Neurons need a little help to fight toxic insults.  Early on, neurons can cope with the problems, but later, they become overwhelmed," he says.  Treatments that reduce overactive nerve signaling may give neurons the help they need to survive, at least for a while.

Abnormal calcium signaling in neurons has been implicated in a variety of other neurological disorders, including Alzheimer's disease and Parkinson's disease.  Therefore drugs that reduce calcium signaling might be useful not just in HD but also in other diseases, Dr. Botas says.

The researchers are now planning studies that will test calcium channel blockers and other drugs that reduce nerve signaling in animal models of HD.  If the results of those studies are promising, the investigators hope to eventually begin studying the drugs in people who are at risk of the disease. 

The NINDS is a component of the National Institutes of Health (NIH) within the Department of Health and Human Services.  The NIH — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research. It investigates the causes, treatments, and cures for both common and rare diseases.  For more information about NIH and its programs, visit

-By Natalie Frazin

[1]Romero E, Cha G-H, Verstreken P, Ly CV, Hughes RE, Bellen HJ, Botas J.  "Suppression of neurodegeneration and increased neurotransmission caused by expanded full-length huntingtin accumulating in the cytoplasm."  Neuron, January 10, 2008, Volume 57, Issue 1, pp. 27-40

Last Modified June 26, 2008