Attacking muscle diseases like ALS by clearing protein clumps

Nerve cells
UNC researchers envision a drug that reverses protein clumping and restores muscle function in people with degenerative muscle disease.

Researchers have identified a process that promotes the protein clumping characteristic of degenerative diseases. While the work is in early stages, a team from the University of North Carolina envisions an injectable or oral drug that could treat amyotrophic lateral sclerosis (ALS) and sporadic inclusion body myositis (sIBM).

The protein, TDP-43, usually works in the cell’s nucleus, where it is thought to regulate gene expression. But in people with degenerative diseases, it moves into the main body of the cell, where it clumps. This leads to cell death of motor neurons in ALS and muscle cells in sIBM.

"We suspect that getting rid of this abnormal TDP-43 clumping could be a potential therapy for these diseases," said senior author Todd Cohen, an assistant professor of neurology at UNC, in a press release.


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Cohen’s team found in an earlier study that a chemical process called acetylation causes TDP-43 to detach from RNA and leave the nucleus. In their new study, the team moved beyond cells grown in lab dishes and spinal motor neurons from ALS patients and looked at mouse models.

They injected acetylated TDP-43 proteins into the mice’s muscle cells, which quickly aggregated outside the nucleus. The team also found that the cells were actively trying to clear the clumps. Furthermore, they discovered that the protein heat shock factor 1 helped this process along. The team is now on the hunt for compounds that have the same anti-clumping effect as HSF-1.

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While the study, published in Nature Communications, focuses on sIBM, the team’s findings may have implications for ALS.

"I tend to see sIBM and ALS as resulting from essentially the same TDP-43-related pathological process—the clumping effect—but in different cell types," Cohen said. "The advantage of studying sIBM is that muscle cells are much more accessible than are motor neurons, which are affected in ALS. Once we understand the role of TDP-43 in sIBM, we can also study this process in neurons."

"Ideally we would give someone with sIBM a drug that boosts these anti-aggregation systems, and the result would be the removal of the TDP-43 aggregates and the eventual recovery of muscle function," Cohen said. "We hope and suspect that a similar approach would work for neurons in ALS, too."

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