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NIH Research Matters

April 30, 2007

Study Links Faulty DNA Repair to Huntington’s Disease

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.

Image of a broken helix spiraling up from a mouse's head.

Artistic rendering of a broken DNA helix emanating from a mouse nerve cell. Researchers recently uncovered evidence that faulty DNA repair may be to blame for the onset of Huntington's disease symptoms. Image courtesy of Cynthia McMurray.

Huntington's disease results from the degeneration of brain cells, called neurons, in certain areas of the brain. Huntington's disease symptoms usually appear in middle age. Symptoms include mood swings, depression, irritability, uncontrolled movements and trouble driving, learning new things, remembering a fact or making a decision. As the disease progresses, it becomes more difficult to concentrate or control muscle movement to do even basic things like walking and swallowing. There's currently no way to stop or reverse the course of the disease.

Researchers knew that people with Huntington's disease have a version of a gene called huntingtin that carries an extra segment. If the segment is too large, the gene produces a faulty protein that has a destructive effect in the brain. Dr. Cynthia T. McMurray, a professor of pharmacology at the Mayo Clinic, led a research team exploring how this segment expands. Their work was funded by NIH's National Institute of General Medical Sciences (NIGMS), National Institute of Neurological Disorders and Stroke (NINDS) and National Institute of Environmental Health Sciences (NIEHS).

The researchers genetically engineered mice carrying a version of the human huntingtin gene with an inserted segment that would be large enough to cause Huntington's disease in humans. As they reported in an advanced online publication in the journal Nature on April 22, 2007, after a few months, the segment had expanded. They also observed an increase in "oxidative lesions" in the mouse DNA. Oxidative lesions are a type of DNA damage caused by byproducts of the oxygen we breathe.

To see if oxidative lesions played a role in expansion of the extra DNA segment, the researchers next deleted OGG1, a key enzyme in the body's oxidative lesion repair system. They found that, without OGG1, the bulk of the DNA's oxidative lesions remained untouched, and the inserted segment either didn't grow at all or grew far less than in mice carrying a working version of OGG1.

The researchers went on to perform other experiments to support the idea that while doing its part in removing oxidative lesions, OGG1 triggers the expansion of the DNA segment associated with Huntington's disease. Oxidative lesions accumulate in everyone, but because most people's huntingtin gene lacks this extra segment to begin with, it isn't prone to expansion.

The researchers still aren't sure exactly how OGG1 causes the expansion of the huntingtin gene segment. This study nevertheless suggests that OGG1 might offer a target for the development of new Huntington's disease treatments. McMurray's team is already screening for small molecules that block OGG1 function.

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Editor: Harrison Wein, Ph.D.
Assistant Editors: Vicki Contie, Carol Torgan, Ph.D.

NIH Research Matters is a weekly update of NIH research highlights from the Office of Communications and Public Liaison, Office of the Director, National Institutes of Health.

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This page last reviewed on December 3, 2012

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