The ALS Association

ALS Ice Bucket Challenge Progress

Studies Highlight Findings Involving the C9orf72 Gene Mutation

November 4, 2013

Three studies supported by The ALS Association expand the understanding of the effects of the C9orf72 gene mutation, the most common genetic cause of ALS.

“These studies provide important new insights into this gene,” said Lucie Bruijn, Ph.D., Chief Scientist for The Association. “By learning more about the all consequences of the mutation, we can look for multiple therapies to address them.”

Researchers showed in the first study that the mutant gene is modified to reduce the amount of protein that is made from it. This modification, called histone methylation, affected the mutant copy of the gene but not the normal copy also carried by virtually all people who carry the mutation. It is possible that this modification accounts for the lower levels of the C9orf72 protein seen in people with ALS. The function of the protein is unknown, but it is possible that a decrease in the protein may be harmful to cells. The researchers saw this methylation change not only in neurons, but also in blood cells. This means that methylation might be valuable as a “biomarker” to detect the presence of the gene mutation. Biomarkers serve as an indicator of a particular condition in the body.  This study was conducted by Veronique Belzil, Ph.D., and Peter Bauer, M.D., Ph.D., under the guidance of Leonard Petrucelli, Ph.D., all of the Mayo Clinic in Jacksonville, Fla. Dr. Petrucelli’s research is funded by The Association. This study was published in the journal Acta Neuropathologica.

In the second study, Tania Gendron, Ph.D., and graduate student Kevin Bieniek, together with  Dr. Petrucelli and Dennis Dickson, M.D., also of the Mayo Clinic Jacksonville, showed that the C9orf72 mutation is “read” by the protein-making machinery of the cell in an unusual way. The DNA that forms all genes has two strands, which pair together. Normally, only one strand is used to form the “messenger” molecule RNA, which ultimately provides the information for making the protein. When the C9orf72 gene is mutated, that messenger RNA becomes very long and tangled, presumably leading to many of the problems seen in ALS neurons. In this study, the authors found that not just one strand, but both strands of the DNA, were used to form messenger RNA, and that RNA from the usually silent strand also became tangled. In addition, this RNA was “read” by the protein-making machinery as well, forming unusual short proteins called “RAN peptides.” The contribution of RAN peptides to ALS is unknown and is the subject of intense investigation. This study was also published in Acta Neuropathologica.

“These results give us new leads in our pursuit of understanding the consequences of the C9orf72 mutation,” Dr. Bruijn said. “Our next step is to determine just how significant each of these changes is and whether they can be mitigated by development of new therapeutics.”

Researchers involved in the third study showed that the tangles of RNA caused by the C9orf72 mutation could be reduced using “antisense” molecules that bind to and help degrade RNA. Working in cultured neurons derived from people with this mutation, antisense treatment also corrected several mutation-induced abnormalities in the neurons, indicating the potential for antisense treatment for people with C9orf72-caused ALS. The study was conducted by Dhruv Sareen, Ph.D., under the leadership of Robert Baloh, M.D., both of Cedars-Sinai Medical Center in Los Angeles, Calif., with contributions from Dr. Petrucelli.

“Antisense therapy is a highly promising approach to treatment of ALS due to known gene mutations,” Dr. Bruijn noted. “The Association is at the forefront of support for developing this type of therapy, and these results give us still more hope that it may be a valuable treatment.”

Read the press release.

Related links:

Antisense for the Most Common ALS Gene Appears Safe in Initial Study

C9orf72 Symposium Highlights New Ideas in Understanding and Treating ALS and FTD

New Genetic Mutation Identified: the Most Common Cause of FTD and ALS Accounting for as Much as One Third of All Familial ALS

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