DNA Damage in ALS

A failure to repair damaged DNA appears to play an important role in amyotrophic lateral sclerosis (ALS), an MDA-supported team of researchers reports.

DNA, the molecule that encodes the "genetic blueprint" for life, often sustains damage, but various mechanisms employed by the cell typically repair it right away. When the cell's DNA repair capabilities are impaired, however, it leads to the progressive loss of structure or function of nerve cells (neurodegeneration) that is seen in ALS and other diseases with neurological components.

Li-Huei Tsai at the Massachusetts Institute of Technology in Cambridge, Mass., and colleagues, showed that ALS-causing mutations in the FUS gene impair the DNA damage response in motor neurons, the muscle-controlling nerve cells that die in ALS.

The findings link DNA damage with ALS and suggest that therapies designed to boost the DNA repair process in motor neurons may be effective treatments for the disease.

The team published its findings online Sept. 15, 2013, in Nature Neuroscience. Also see DNA Damage May Cause ALS. MDA supported Eric J. Huang for his work on this project.

The FUS gene plays an important role in DNA repair

In cell culture experiments, the researchers observed that FUS protein, encoded by the FUS gene, moves almost immediately to the site of DNA damage. There it interacts with other proteins, including one called HDAC1, to activate DNA repair pathways.

When the researchers decreased levels of FUS protein, the damage response was dampened and the amount of accumulated DNA damage increased.

Although previous studies have linked the FUS gene with DNA repair, the research team showed that most ALS-causing mutations in FUS occur in specific areas of the gene that are necessary for its interaction with HDAC1.

DNA damage in people with ALS

In postmortem samples taken from the brains of people who had ALS, the researchers observed high levels of DNA damage. In addition, they note that in previous studies markers of DNA damage appear to be higher in the spinal cords of people with ALS than in people without the disease.

The researchers report that their findings support a connection between FUS dysfunction and human disease, and suggest that impaired DNA repair may make motor neurons more vulnerable to the toxic conditions and stress that occur in ALS.

Further studies are needed to determine whether strategies that aim to boost the DNA repair process may be effective in ALS.

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