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Nov 5

Molecular differences between C9orf72 mutation-associated and sporadic ALS

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Molecular differences between C9orf72 mutation-associated and sporadic ALS

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Sporadic and familial forms of ALS are essentially identical on the outside, but new work led by Packard scientist Leonard Petrucelli has found differences at the molecular level between individuals with sporadic ALS and ALS caused by a mutation in the gene C9orf72, the most common known genetic cause of the disease.

Petrucelli, a neuroscientist at the Mayo Clinic in Jacksonville, Florida, and colleagues found that both groups of people with ALS had abnormalities in the amount and processing of RNA molecules, although the researchers also identified more subtle differences between the two groups. These results,published on July 20 in Nature Neuroscience, indicate that ALS might have multiple causes that lead to a final, common pathway involving alterations in RNA processing and motor neuron death.

Both sporadic cases of ALS, which make up 90% of individuals diagnosed with the disease, and familial forms of the disease seem to involve RNA abnormalities, which include clumps of RNA and misfolded proteins that form when the cell is under stress but don’t disappear when the stress is gone. This, along with other factors, means that the RNA molecules aren’t around to do their normal job of turning genes into proteins.

Petrucelli and colleagues used next-generation RNA sequencing to study how the C9orf72 mutation possibly affected processing of many different genes, and compared this to transcription in people with sporadic ALS as well as healthy controls. Using samples from the cerebellum and frontal cortex from tissue obtained at autopsy, the researchers identified genes in each sample that were differentially processed  in people with c9ALS and sALS, while only a subset was shared between groups.   The genetic data was deposited in a freely available DNA repository so that other researchers can use this information.

Both groups of patients showed defects in alternative splicing and in alternative polyadenylation, both of which allow a single gene to code for several different proteins. When Petrucelli and colleagues looked at splicing alterations as networks of changes, the differences they found between people with c9ALS and sALS further supported the divergence observed between the two groups. Overall, the altered RNA processing seen in both groups was caused by different groups of genes that were part of different biological pathways.

The results are important for studying ALS and developing treatments for the disease because it indicates that future therapies may need to be tailored to the specific genetics underlying the degeneration of a person’s cells.

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