The ALS Association

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Carrie Munk
The ALS Association
(571) 319-3047



New Disease Mechanism Revealed for C9orf72 Gene Mutations

Washington, D.C. (March 21, 2016)— In a new study funded by The ALS Association, Yong-Jie Zhang, Ph.D., Leonard Petrucelli, Ph.D., and their research team from the Mayo Clinic in Jacksonville, Fla. have uncovered a new and potentially important disease mechanism that occurs in the C9orf72 gene, the most common genetic form of ALS. This study was published today in top-tiered scientific journal Nature Neuroscience.

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 often leads to total paralysis and death 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 mutations in the C9orf72 gene are responsible for up to 40 percent of familial ALS and 6 percent of sporadic ALS, as well as a fraction of cases of frontotemporal dementia (FTD). The expanded gene creates abnormally long molecules of the chemical messenger RNA. The RNA, in turn, gives rise to unusual proteins called dipeptide repeat proteins (DPRs), including ones made from the amino acids glycine and alanine. In this new study, first author Yong-Jie Zhang, Ph.D., and his research colleagues, explored the consequences of glycine-alanine DPRs in mice.

The team showed that the presence of the DPRs, even in the absence of the mutant gene or RNA, caused neurons to degenerate in the brains of mice, leading to both motor and cognitive deficits suggestive of ALS and FTD. This suggests that the DPRs contribute directly to the toxicity associated with the gene mutation. The DPRs are linked to a protein called HR23, which is critical for breakdown of defective proteins. The same binding between HR23 and DPRs was observed in people carrying the expanded C9orf72 gene, suggesting this binding may contribute to the human disease. Cells in culture that created excess HR23 were protected from DPR-related injury, suggesting that blocking the interaction of HR23 and DPRs may be therapeutic in ALS and FTD.

“This important study provides new data to enhance our understanding of C9orf72-related ALS,” said ALS Association Chief Scientist Lucie Bruijn, Ph.D., M.B.A. “The identification of this new disease mechanism will allow us to determine whether blocking the interaction between DPR’s and HR23 may provide a new avenue for treatment development.”

About The ALS Association
The ALS Association is the only national non-profit organization fighting Lou Gehrig’s Disease on every front.  By leading the way in global research, providing assistance for people with ALS through a nationwide network of chapters, coordinating multidisciplinary care through certified clinical care centers, and fostering government partnerships, The Association builds hope and enhances quality of life while aggressively searching for new treatments and a cure.  For more information about The ALS Association, visit our website at

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