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.

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New Protein Target Emerges for C9orf72 the Most Common Genetic Form of ALS

research news banner 2015Targeting a single protein, called SUPT4H1, reduces the levels of the three toxic entities created by the C9orf72 gene expansion, the most common genetic cause of ALS, according to a study published in the journal Science. The finding suggests that SUPT4H1 may be a promising candidate for therapy development for people whose disease is caused by expansion of the C9orf72 gene. The study was supported by The ALS Association and led by senior investigators Leonard Petrucelli, Ph.D., of the Mayo Clinic in Jacksonville, Fla and Aaron Gitler, Ph.D., of Stanford University in Stanford, Calif., along with co-lead investigators Nicholas Kramer, Ph.D., Yari Carlomagno, Ph.D., Fen-Biao Gao, Ph.D., and Yong-Jie Zhang, Ph.D.

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New C9orf72 Mouse Models Show Neurodegeneration from Most Common Genetic Cause of ALS

research news banner 2015Two 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.

Continue reading New C9orf72 Mouse Models Show Neurodegeneration from Most Common Genetic Cause of ALS

New Mouse Model of the Most Common Genetic Cause of ALS

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.

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.