Huntington’s Disease :: Faulty DNA Repair to Huntington’s Disease Onset

Huntington’s disease, an inherited neurodegenerative disorder that affects roughly 30,000 Americans, is incurable and fatal. But a new discovery about how cells repair their DNA points to a possible way to stop or slow the onset of the disease.

The research was funded by the National Institutes of Health (NIH).

?As so often happens, basic research on a fundamental biological process?in this case, enzymes involved in DNA repair?leads to new insights about how diseases arise and new approaches for treating or preventing them,? said NIH Director Elias A. Zerhouni, M.D.

The study was published April 22 as an Advanced Online Publication in Nature and led by Cynthia T. McMurray, Ph.D., a professor of pharmacology at the Mayo Clinic in Rochester, Minnesota.

Unlike most inherited diseases, Huntington’s disease symptoms usually don’t appear until middle age, leading scientists to wonder what triggers the disease onset and whether it can be halted?or at least slowed down.

People with the disease have a version of a gene called huntingtin that carries an extra segment with a particular sequence of repeated subunits. If the segment is too large, the gene produces a faulty protein that has a destructive effect in the brain.

?Huntington’s disease is a progressive disease, but nobody knows exactly why,? said McMurray. ?Our work supports the idea that the disease progresses when the extra segment expands over time in non-dividing cells such as nerve cells.?

McMurray’s study shows that the inserted segment grows when cells try to remove oxidative lesions, which are caused by byproducts of the oxygen we breathe. DNA repair enzymes initially keep oxidative lesions in check, but over time, increasing numbers of lesions overwhelm the repair systems. Oxidative lesions also accumulate in people who do not have Huntington’s disease, but because their huntingtin gene lacks the extra segment it is not prone to expansion.

While scientists have long suspected that oxidative lesions play a role in Huntington’s disease, the specific role of the lesions has remained elusive until now.

?Nobody has connected the dots before,? said McMurray.

The NIH components that contributed to this research are the National Institute of General Medical Sciences, the National Institute of Neurological Disorders and Stroke and the National Institute of Environmental Health Sciences.

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