The ALS Association

Ice Bucket Challenge Progress

Unexpected Discovery Could Indicate New Target for ALS Therapy

February 12, 2013

Researchers funded by The ALS Association have discovered evidence of an unexpected cellular process in some people with amyotrophic lateral sclerosis (ALS). The results should allow researchers to better track the disease in these people and may offer a new target for developing therapy.

The research showed that mutations in the C9ORF72 gene cause cells to create an unusual protein-like molecule that is not found in healthy individuals or in people with other neurologic diseases. Mutations in the C9ORF72 gene are responsible for between 20% and 40% of familial ALS. The mutation causes cells to create long, repetitive chains of a cellular molecule called RNA. The researchers found that when the cell’s protein-making machinery latches on to this repetitive RNA, it creates a protein-like chain called a RAN-translated peptide, which the researchers have termed C9RANT. The peptide’s own repetitive structure makes it stick to itself, and the researchers found clumps of the peptide in the brains of people who had died of ALS.

It is still unknown whether these peptides are contributing to disease or are uninvolved in it. But in either case, they offer researchers a specific marker for ALS caused by the C9ORF72 gene and potentially a way to measure disease activity and response to therapy.

“This discovery highlights the complexity of the ALS disease process,” said ALS Association Chief Scientist Lucie Bruijn, Ph.D. “But it also may provide a new window into that process and offer a way to track how neurons are responding to treatments in this form of the disease. In that respect, this finding could be an important step forward.”

The study was conducted by Peter Ash and Kevin Bieniek under the guidance of Leonard Petrucelli, Ph.D., of the Mayo Clinic in Jacksonville, Fla., and was published in the journal Neuron. The ALS Association provided support for this research to Dr. Petrucelli and to Kevin Boylan, M.D., also of the Mayo Clinic and also an author in the study.

“Just as new therapies are being developed to break down the protein aggregates associated with Alzheimer’s and Parkinson’s diseases, developing a therapeutic strategy to target C9RANT aggregates may also prove beneficial,” said Dr. Petrucelli, Chair of Neuroscience.

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