Mayo Clinic Study Of Defective Gene That Causes Huntington's Sheds New Light On Disease

The results, published in the November issue of Nature Genetics, shed light on how the molecular pathology of Huntington’s disease causes the loss of brain tissue over time in patients. Their results could change the view of how a defective gene causes the disorder.

About 30,000 people in the United States have Huntington’s disease and children of people with HD have a 50 percent chance of inheriting the defective gene. The disease is progressive and there is currently no known cure. The recent results may have a big impact on how we approach therapy and reset thinking on the aberrant interactions of the full-length mutant gene product.

The study was led by Cynthia T. McMurray, Ph.D., together with Roy Dyer, Ph.D., of the Mayo Clinic Department of Molecular Pharmacology and Experimental Therapeutics.

The genetic defect causing HD is an expansion of an amino-acid stretch in a gene product called Huntingtin. Since its discovery in 1993, researchers have focused a great deal of attention on how the mutations causes neurons to die.

The prominent theory to date was that clipping of the mutant gene product generated a small "toxic fragment" in cells. The defective protein from the mutant Huntington’s gene contains an abnormal section. Therefore, fragments with the abnormal section accumulate and become toxic to brain cells. If correct, therapy might aim to block the molecules that do the cutting to prevent the release of the toxic fragment.

However, the recent study suggests a different pathway. Dr. McMurray and her colleagues find in autopsy tissue from the brains of HD patients that the mutant protein is actually resistant to getting chopped up much more than its normal counterpart. As a result, the full-length protein begins to accumulate in the neuron with time, consistent with a late-onset disorder of HD. Further, they show that the accumulation of the mutant protein grabs the normal counterpart in the cell. Thus, expression of the mutant may act to "knockout" the function of the HD protein which is essential to cell function. If correct, then therapy may involve approaches to disruption of the clumps.

The recent study suggests the full-length protein is responsible for toxicity rather than a small toxic fragment.

"Our results shift the thinking about the mechanism of Huntington’s disease therapy,"' says Dr. McMurray, the senior author of the study. The full-length protein may be capable of grabbing partners that it cannot if it is only a small fragment. If the mutant protein is not clipped, then it is expected to reside in a particular compartment in the cell called the "cytoplasm." Therefore, scientists may redirect focus on critical targets grabbed by the mutant protein found in this compartment.

"Our results suggest that trying to find ways to prevent the chopping up of the mutant protein won’t be the most effective strategy to help treat the disease," said Dr. McMurray.

Instead, Dr. McMurray suggests that approaches aimed at developing molecules to prevent the mutant from grabbing cellular targets may be most effective. She is working on such approaches.

HD is an inherited, adult-onset disease of the central nervous system characterized by involuntary movements, cognitive impairment progressing to dementia and mood disturbances -- these symptoms are due to extensive loss of brain neurons.