ALS Gene C9orf72 Damages DNA Revealing a New Disease Pathway

The most commonly inherited gene in familial ALS, C9orf72, points to DNA damage causing oxidative stress, according to a new study funded by The ALS Association. The study was published in the journal Neuron and led by principle investigator Fen-Biao Gao, Ph.D. and first author Rodrigo Lopez-Gonzalez, Ph.D. from the Department of Neurology at University of Massachusetts Medical School in Worcester, Mass. Findings from this paper point to DNA damage as a disease pathway of C9orf72-related ALS.

ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Eventually, people with ALS lose the ability to initiate and control muscle movement, which leads to total paralysis and death, usually within two to five years of diagnosis. For unknown reasons, veterans are twice as likely to develop ALS as the general population. There is no cure, and only one drug approved by the U.S. Food and Drug Administration (FDA) modestly extends survival.

Expansion of the C9orf72 gene is the most common genetic cause of ALS. The expansion causes production of unusual “dipeptide repeat proteins,” and earlier work has suggested these proteins may be toxic to motor neurons. Here, the investigators showed that there was an increase in the level of DNA damage in cultured cells derived from people with ALS due to the gene mutation. They also showed that the proteins caused DNA damage in normal cells, suggesting that the proteins were directly responsible for the damage seen in ALS cells. They also found that the proteins interfered with protein production in the cell’s powerhouses, called mitochondria. This interference led to an increase in oxidative stress, which led to damage to DNA. Oxidative stress is caused by the accumulation of destructive molecules called free radicals. Reducing the oxidative stress, they showed, reduced the DNA damage. This study points to DNA damage as a disease mechanism for C9orf72-associated ALS. Reducing pathways that cause DNA damage, like oxidative stress and mitochondrial dysfunction, could serve as potential ALS therapeutic strategies.

“The results from this important study further strengthen the case that oxidative stress contributes to ALS due to the C9orf72 gene mutation,” commented Lucie Bruijn, Ph.D., M.B.A., The ALS Association Chief Scientist. “The detection of DNA damage in this cell model is potentially significant, as strategies to reduce DNA damage are the focus of drug development in other fields, and that body of knowledge may accelerate development of new treatments for this form of ALS.”

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