DNA Repair as Key to Huntington’s Disease

Huntington’s disease (aka Huntington’s chorea) is caused by a trinucleotide repeat expansion in the Huntingtin (Htt) gene. The resultant mutant Huntingtin (mHtt) gene is responsible for neuronal cell death. Until now, no one knew how the gene expansion occurs.
A new study from the Mayo Clinic, the National Institutes of Health (NIH) and University of Oslo, Norway describes the mechanism:

“We showed that when single-strand breaks in DNA caused by oxidative lesions were repaired, the Huntington’s gene continued to add extra replacement segments,” explains Cynthia McMurray, Ph.D., a Mayo Clinic molecular biologist who led the study team. “Over time, this expansion — especially in nerve cells — becomes toxic.”
The finding is significant because so little is known about Huntington’s. According to Dr. McMurray, the finding is the first confirmed connection between the DNA repair and progression of the disease. Leaders at the NIH, which sponsored the study, are optimistic the findings will lead to advances.
“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 Zerhouni, M.D.
In their study of transgenic mice that carried the human Huntington’s gene, the researchers noted that the repeated tracts of replacement repair segments seem stable until the animals reach about 4 months of age. After that point — which represents middle age for a mouse — the segments expand and continue to do so as the animals age. Researchers also showed that the expansion of the tracts — an inherited characteristic — also caused toxicity in cells that cannot expand, such as nerve cells. The result is that cell death acceleration is directly proportional to the additional repeated lengths.
In a further step, the team eliminated a key enzyme (OGG1) related to DNA repair for oxidative lesions and found that it stopped or greatly reduced segment growth. This may position OGG1 as a target candidate for interventional therapies to disrupt the onset of the disease.

Press release: Mayo Clinic Discovers DNA Repair as Key to Huntington’s Disease …