Dr. McMurray and her colleagues have identified how this works. They found that a DNA repair enzyme causes continued CAG repeat expansion. As we age, our brain cells experience more oxidative damage, including damage to DNA.
Energy for cellular processes is produced in the mitochondria. During the process, free radicals are produced. This is a molecule of oxygen with only one electron, not with two electrons that are bonded together which is the normal form of oxygen. This means it can go scavenge for other molecules to bond with. Normally this isn't a problem because nearby antioxidants will bond with the free radicals and render them harmless. When there are too many free radicals and not enough antioxidants, they can do a lot of damage. This process is called oxidative stress.
As we age, our energy metabolism gets less efficient; free radicals go scavenging and can destroy cellular compounds and damage proteins, lipids, and DNA, and lead to cell death - especially in the brain which generates more oxidative by products than other organs of the body.
When a strand of DNA breaks, an enzyme called 7,8-dihydro-8-oxoguanine-DNA glycosylase (OGG1)repairs it. However, when the HD gene is involved, more and more CAG repeat sections just keep getting added, leading to greater toxicity and cell death. The researchers found that when OGG1 was eliminated, this expansion either didn't occur or was greatly reduced. This suggests that a compound which blocks OGG1 might be a treatment, although not a cure.
The take home message for those at risk and with the gene is to eat a diet rich in antioxidants.
Although oxidative damage has long been associated with ageing and neurological disease, mechanistic connections of oxidation to these phenotypes have remained elusive. Here we show that the age-dependent somatic mutation associated with Huntington's disease occurs in the process of removing oxidized base lesions, and is remarkably dependent on a single base excision repair enzyme, 7,8-dihydro-8-oxoguanine-DNA glycosylase (OGG1). Both in vivo and in vitro results support a 'toxic oxidation' model in which OGG1 initiates an escalating oxidation–excision cycle that leads to progressive age-dependent expansion. Age-dependent CAG expansion provides a direct molecular link between oxidative damage and toxicity in post-mitotic neurons through a DNA damage response, and error-prone repair of single-strand breaks.
The Press Release
Mayo Clinic discovers DNA repair as key to Huntington's disease
Poor gene repair may point to cause of incurable disease
ROCHESTER, Minn. -- Mayo Clinic researchers, along with collaborators from the National Institutes of Health (NIH) and University of Oslo, Norway, have discovered that a miscue of the body’s genetic repair system may cause Huntington’s disease, a fatal condition that affects 30,000 Americans annually by destroying their nervous system. Until now, no one knew how Huntington’s begins, only that it is incurable. The findings appear in the online issue of the journal Nature.
"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.
Others on the research team included primary researcher Irina Kovtun, Ph.D., Mayo Clinic; Yuan Liu, Ph.D., and Samuel H. Wilson, M.D., National Institute of Environmental Health Sciences; and Magnar Bjoras, M.Sc., and Arne Klungland, Ph.D., University of Oslo, Norway.
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