The ALS Association

Ice Bucket Challenge Progress
Carrie Munk
The ALS Association
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New C9orf72 Mouse Models Show Neurodegeneration from Most Common Genetic Cause of ALS

Washington, D.C. (April 21, 2016)— Two independent research studies both funded by The ALS Association, including principal investigator Laura Ranum, Ph.D., of the University of Florida in Gainesville and the other study led by Don Cleveland, Ph.D., of University of California San Diego in San Diego and Clotilde Lagier-Tourenne, M.D., Ph.D., of Massachusetts General Hospital in Boston, have developed new mouse models of the C9orf72 mutation that show neurodegeneration and motor and cognitive deficits reminiscent of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In addition, one group showed that these effects could be ameliorated in mice by antisense therapy against the mutant gene.

“These studies represent significant progress in understanding the consequences of the C9orf72 gene mutation and in developing a therapy against it,” said Lucie Bruijn, Ph.D., M.B.A., Chief Scientist for The ALS Association.

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, whose normal function is unknown, are the most common genetic cause of ALS and a related neurodegenerative disorder, frontotemporal dementia. The gene expansion was discovered in 2011, and other groups have developed mouse models of the gene and begun to explore the consequences of the mutation. The new models will add significantly to the ability to exhibit ALS due to C9orf72 mutations.

In the first of the new studies, Yuangjing Liu, Ph.D., along with principal investigator Laura Ranum, Ph.D., of the University of Florida and colleagues, injected mouse cells with a “bacterial artificial chromosome,” a carrier for large amounts of DNA that carried the full-length C9orf72 gene. The mice developed the cellular hallmarks of the mutation, including accumulations of RNA called “foci” and expression of non-standard proteins (RAN proteins), both of which are thought to contribute to disease development. They also showed reduced survival, paralysis, motor neuron loss, anxiety (a cognitive feature associated with FTD) and neurodegeneration in multiple brain regions.

In the second study, co-first authors Jie Jang, Ph.D., Qiang Zhu, Ph.D., and Tania Gendron, Ph.D., along with principal investigators Don Cleveland, Ph.D. and Clotilde Lagier-Tourenne, M.D., Ph.D., and colleagues, created multiple mouse models, including ones with reduced or no expression of the normal C9orf72 gene and others expressing the mutant gene. Drs. Jang, Zhu and Cleveland are from the University of California San Diego, Dr. Gendron is from the Mayo Clinic in Jacksonville, Fla., and Dr. Lagier-Tourenne is from Massachusetts General Hospital in Boston. Qiang Zhu, Ph.D. is an ALS Association funded Milton Safenowitz Postdoctoral Fellow. Founded by the Safenowitz family through the Greater New York Chapter of The ALS Association and in memory of Mr. Safenowitz, who died of ALS in 1998, these awards are to encourage and facilitate promising young scientists to enter the ALS field.

Dr. Cleveland’s laboratory is part of The Neuro Collaborative. The ALS Association Golden West Chapter and patient advocate Jim Barber partnered to build the Neuro Collaborative concept in 2014. With funds received from donors to the ALS Ice Bucket Challenge, The ALS Association committed $5 million dollars to the Neuro Collaborative in 2014. In addition, The ALS Association Orange County and Wisconsin Chapters have contributed to this important initiative.

Finding from these mouse models demonstrate that neither partial nor complete loss of gene expression lead to neurodegeneration. Instead, as in Dr. Ranum’s study, expression of the mutant gene led to ALS-like and FTD-like features, including anxiety, though not loss of motor neurons. Importantly, those features could be significantly reduced by treatment with antisense oligonucleotides (ASOs), which allowed expression of the normal gene but prevented accumulation of the long RNA strands produced from the mutant gene. ASO technology works to eliminate mutant protein by preventing it from being created.

“These models provide important new ways to learn more about the effects of the C9orf72 gene mutation and will contribute directly to further development of antisense therapy approaches to reduce those effects,” Dr. Bruijn said. “Interestingly, these models and those C9orf72 mouse models published earlier, all present slightly differently. Understanding these differences may shed further light on the disease process.”

Click here and here for more information of previously published C9orf72 mouse models.

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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