Protein Clumps That Turn Toxic in ALS Also Found in Healthy Muscle Undergoing Repair, Study Reports

Protein Clumps That Turn Toxic in ALS Also Found in Healthy Muscle Undergoing Repair, Study Reports
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While TDP-43 aggregates are associated with amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, researchers have found that these protein clumps are also involved in the regeneration of  healthy skeletal muscle.

This finding — that abnormal TDP-43 aggregates temporarily form to repair damaged muscle — may open new lines of research into the underlying mechanisms of ALS development, and into new ways of clearing their toxic buildup in disease.

The study, “TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle,” was published in the journal Nature.

The accumulation and aggregation of specific proteins in nerve cells is a hallmark of neurodegenerative diseases. These aggregates — which can form specific insoluble fibrous structures known as amyloids — are believed to be toxic because they are thought to lead to the nerve cell death and neurodegeneration associated with these conditions.

In ALS, the main component of these toxic aggregates is TDP-43, a RNA-binding protein that regulates RNA — a molecule generated from DNA that serves as a template for the production of a specific protein.

While usually located in the nucleus of a cell (the central compartment where the DNA is located), TPD-43 can be found in clumps outside the nucleus in nerve cells of ALS patients.

Researchers at University of Colorado Boulder, however, made an unexpected discovery that challenges the notion that these protein aggregates are characteristically toxic.

The team found that TDP-43 aggregates outside the nucleus were also present in healthy muscle cells, and were associated with muscle formation and regeneration in both mice and humans.

A detailed analysis of the TDP-43 protein in muscle tissue grown in the lab showed that while TDP-43 was usually located inside the nucleus, muscle injury led to its accumulation outside the nucleus, where it formed temporary granular structures bound to RNA molecules — which the researchers called myo-granules.

These myo-granules shared several features with the toxic aggregates associated with ALS, including amyloid-like properties. With progressive muscle growth and recovery from injury, they disintegrated and TDP-43 returned to the nucleus.

“These amyloid-like aggregates, which we thought were toxic, seemed to be a normal part of muscle formation, appearing at a certain time and then disappearing again once the muscle was formed,” Brad Olwin, one of the study’s senior author, said in a press release.

Further analysis showed that lowering TDP-43 levels in these muscle cells impaired muscle growth, and that the RNA molecules that TDP-43 aggregates bonded with were involved in muscle formation and its ability to contract.

These data reveal that TDP-43 myo-granules may regulate muscle regeneration and formation through their binding to specific RNA molecules that are involved in these processes.

The team also found that mice with a mutation known to be associated with ALS (and other TDP-43–linked conditions in humans) had an increased number of TDP-43 myo-granules compared to healthy mice.

This suggests that excessive generation— or improper clearance — of normal TDP-43 myo-granules could lead to the formation of the toxic TDP-43 aggregates that characterize these diseases.

Joshua Wheeler, the study’s co-first author, noted that these myo-granules are likely to be formed naturally after vigorous exercise or weight training, which stimulates muscle growth and repair.

“If they normally form and go away, something is making them dissolve,” Olwin said. “Figuring out the mechanisms involved could potentially open a new avenue for treatments.”

The team plans to find out more about the role of TDP-43 clumps and evaluating whether this process also happens in the brain after injury, and whether it is linked to the development of Parkinson’s and Alzheimer’s disease, both characterized by the formation of protein amyloids.

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