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 study was published in Nature.

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.

A study, led by Cynthia T. McMurray, at the Mayo Clinic in Rochester, has verified the idea that the disease progresses when the extra segment expands over time in non-dividing cells such as nerve cells.

The study has shown that the inserted segment grows when cells try to remove oxidative lesions. 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 researchers have long suspected that oxidative lesions play a role in Huntington’s disease, the specific role of the lesions has remained elusive until now.

To show that the extra segment enlarges with age, the researchers engineered mice to carry a version of the human huntingtin gene with an inserted segment — one large enough to cause Huntington’s disease in humans. After a few months — when the mice had aged — the researchers analyzed the gene and found that the segment had expanded. They also observed an increase in oxidative lesions in the mouse DNA.

To see if the oxidative lesions played a role in expansion of the extra DNA segment, the researchers next deleted OGG1, a key enzyme in oxidative lesion repair. Without OGG1, the bulk of the DNA’s oxidative lesions remained untouched, and the inserted segment did not grow at all or it grew far less than in mice carrying a working version of OGG1.

These findings show that while doing its part in removing oxidative lesions, OGG1 triggers a far more damaging effect — the DNA expansion associated with Huntington’s disease.

The study suggests that OGG1 might offer a target for the development of new Huntington’s disease treatments.

Source: National Institutes of Health, 2007


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