Protein may drive toxic clump buildup in SOD1-linked ALS, study finds

In amyotrophic lateral sclerosis (ALS) associated with mutations in the SOD1 gene, a protein called S100A6 may contribute to the buildup of toxic protein clumps by interfering with their removal, a study in mouse and cell models suggests.

Researchers found increased expression of the S100a6 gene in mouse models of SOD1-associated ALS. In mouse cells engineered to produce mutant SOD1, increasing S100A6 levels disrupted autophagy, a cellular recycling process that removes damaged or unwanted material, and led to more abnormal clumps of SOD1 protein. Reducing S100A6 levels helped restore autophagy and reduced the clumps.

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These findings suggest that S100A6 could serve as a biomarker for ALS and a potential target for therapies aimed at improving the clearance of abnormal protein clumps, the researchers wrote.

The study, “Unraveling the regulatory nexus of aggrephagy in ALS: identification of novel candidate biomarkers and molecular triggers,” was published in Metabolic Brain Disease.

ALS is a progressive neurological disease in which motor neurons, the nerve cells that control movement, become damaged and die. This leads to worsening muscle weakness and other ALS symptoms.

Mutations in the SOD1 gene cause about 10% to 20% of familial ALS cases and 1% to 2% of sporadic ALS cases. The gene provides instructions for making the SOD1 protein. Mutations can cause this protein to fold incorrectly and form toxic clumps inside cells.

Cells have ways to remove abnormal or unwanted proteins. One is autophagy, a recycling process that breaks down damaged or unneeded parts of cells. Aggrephagy is a type of autophagy that specifically removes clumps of proteins.

When aggrephagy doesn’t work properly, protein clumps may build up and damage motor neurons. However, researchers still don’t fully understand how this process is disrupted in ALS.

Researchers identify genes linked to protein buildup

Researchers in China analyzed publicly available data on gene activity in the spinal cords of SOD1-G93A mice, a commonly used model of SOD1-associated ALS.

The main dataset included eight SOD1-G93A mice and eight control mice. A second dataset, containing six SOD1-G93A mice and three control mice, was used to confirm the findings.

The researchers identified 524 genes with significantly different levels of activity between SOD1-G93A mice and controls. Of these, 49 were identified as candidates potentially involved in aggrephagy. Using several machine-learning methods, they narrowed the list to three genes: Ctsb, Kif11, and S100a6. Two of them, Ctsb and S100a6, showed consistently increased expression in both datasets and were selected for further study.

Ctsb provides instructions for making an enzyme called cathepsin B, which helps break down material inside lysosomes, the cell’s recycling centers. S100a6 provides instructions for making S100A6, a protein that binds to calcium and plays a role in several cellular processes.

Laboratory experiments confirmed increased expression of both genes and higher levels of their proteins in the spinal cords of SOD1-G93A mice and in lab-grown mouse cells resembling motor neurons that produced mutant SOD1.

The team then focused on S100A6, which earlier research had linked to autophagy and SOD1 protein clumping. In the motor neuron-like cells, increasing S100A6 levels impaired autophagy, caused more SOD1 protein clumps to form, and reduced cell viability. Lowering S100A6 levels had the opposite effects.

Boosting cellular recycling reduces SOD1 clumps in cells

The researchers then tested whether boosting autophagy could reverse the effects of excess S100A6. They treated cells producing too much S100A6 with rapamycin, a compound that activates autophagy. The treatment significantly reversed signs of impaired autophagy and reduced SOD1 protein clumping.

Together, the experiments suggest that S100A6 may cause abnormal SOD1 protein clumps to build up by disrupting autophagy.

The team also explored whether Ctsb and S100a6 could serve as biomarkers. A computer model based on their expression showed potential for distinguishing SOD1-G93A mouse samples from controls in the training dataset. However, the datasets were small, and neither gene has been evaluated as a biomarker in body fluids or clinical samples from people with ALS.

The researchers also noted that the SOD1-G93A model represents just one genetic form of ALS and may not reflect the full range of the disease in people. Larger studies, including studies using human samples, are needed to confirm the findings.

Still, the researchers wrote that they identified “Ctsb and S100a6 as potential biomarkers associated with aggrephagy in the SOD1-G93A ALS model, and experimentally validated S100a6 as a critical negative regulator of autophagy that drives SOD1 aggregation.”

“These findings further reveal the crucial role of aggrephagy in ALS, not only laying the foundation for the development of early diagnostic tools based on this mechanism, but also providing an important basis for subsequent research on targeted therapeutic strategies,” the researchers concluded.