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Carrie Munk
The ALS Association
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New Mouse Model of the Most Common Genetic Cause of ALS

Washington, D.C. (May 21, 2015) – Researchers funded by The ALS Association have for the first time created a mouse model of the disease using the mutant C9orf72 gene that displays key elements of disease pathology. The model will likely prove highly valuable in studying the disease process and testing therapies against this form of the disease. The study was published in the journal Science on May 14, 2015.

ALS (amyotrophic lateral sclerosis) is a progressive neurodegenerative disease that affects neurons (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. There is no cure and no life-prolonging treatments for the disease. 

An expansion mutation in the C9orf72 gene is the most common genetic cause of ALS, responsible for up to 40 percent of inherited cases and about 6 percent of sporadic cases. The same mutation is also a cause of frontotemporal dementia (FTD). The mutation increases the number of “CCCCGG” repeat units in the gene from the normal number of less than 10 to hundreds or thousands. This extra DNA leads to production of “sticky” RNA, which may cause disease by sequestering multiple proteins, and to the production of unusual proteins, called RAN proteins, which may themselves be toxic.

The new study was led by Leonard Petrucelli, Ph.D., and conducted by Jeannie Chew, both of the Mayo Clinic in Jacksonville, Fla. The researchers created mice carrying the C9orf72 gene with either two (normal) or 66 (mutant) repeat units. In the mutant mice, cells throughout the central nervous system showed the accumulations of RNA and presence of RAN proteins seen in people with this form of ALS. Affected cells also developed aggregates of the protein TDP-43. Such aggregates are the pathological hallmark of most forms of ALS. Neurons in the nervous system died, and the mice displayed both behavioral and movement symptoms analogous to those seen in ALS and FTD. Other mouse models in development (currently unpublished but presented at scientific meetings) and supported by The ALS Association using the C9orf72 mutation show some interesting aspects of the human disease but have not been able to reproduce this same level of widespread pathology. These models are generated mostly by introducing the repeats onto a bacterial artificial chromosome. In contrast Dr. Petrucelli created their model using adeno-associated virus (AAV) to deliver the mutant gene throughout the mouse nervous system. This illustrates the importance of supporting multiple approaches to generate models for ALS. AAV is being widely studied as a tool for delivering therapeutic genes to the brain and spinal cord, including in ALS.

“This is a significant advance in our quest to understand ALS due to the C9orf72 gene mutation,” said Lucie Bruijn, Ph.D., M.B.A., Chief Scientist for The ALS Association. “This new model will allow us to understand better how the mutation causes disease within a mature nervous system, and what protective mechanisms we can take advantage of to slow the disease process, both for ALS due to this mutation and to other forms of the disease. Just as importantly, we can test treatment strategies that shut down the expression of the mutant gene, which may be the most direct avenue for therapy in this form of the disease.”

Further details of the study and the potential reasons why this approach is more successful in generating a model that looks more like the human disease are discussed in an article on the Alzforum website.

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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