Study links protein, fat regulator to nerve cell damage in ALS

A protein called UBQLN2 is key for regulating both proteins and fat molecules in nerve cells, and disruptions in these activities — particularly the regulation of fat molecules — may play key roles in driving amyotrophic lateral sclerosis (ALS), a study found.

The findings indicate that it may be possible to improve nerve cell health in ALS by modulating the activity of certain fat-destroying enzymes that are normally regulated by UBQLN2, opening potential avenues toward new ALS treatment approaches.

“Here we identify UBQLN2 as a central node connecting [protein and fat] metabolism in ALS,” the researchers wrote.

The study, “UBQLN2 links proteotoxicity with lipid metabolism in neurodegeneration,” was published in Nature Neuroscience. The work was in part funded by the National Institutes of Health (NIH).

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Fats (lipids) and proteins are two of the most important biological molecules. In nerve cells, proteins are key to the ability to send electrical signals, while lipids are essential for maintaining the cell membrane, protecting nerve fibers, and signaling to other nerve cells.

Problems with protein and lipid regulation are thought to play a role in a range of neurological diseases including ALS, a disorder in which the nerves that control movement sicken and die.

The causes of ALS are not fully understood, but several cases are associated with genetic mutations. Mutations in the gene that encodes the protein UBQLN2 are a rare cause of ALS.

Because the UBQLN2 protein plays a key role in quality-control systems that cells use to dispose of unneeded proteins, it’s long been assumed that ALS-causing mutations in UBQLN2 mainly disrupt protein regulation in nerve cells. However, the study showed that UBQLN2 is also essential for regulating lipids in nerve cells.

Through a battery of experiments using cell and animal models, the researchers demonstrated that UBQLN2 normally promotes the degradation of two enzymes, ILVBL and ALDH3A2. These enzymes act to break down certain lipids, so by keeping their levels low, UBQLN2 helps ensure that healthy nerve cells have enough of the lipids they need to carry out their normal functions.

But when UBQLN2 is affected by an ALS-causing mutation, it is no longer able to reduce ILVBL and ALDH3A2 levels. As a result, these enzymes break down too many lipids, leaving nerve cells without enough to stay healthy, ultimately causing them to sicken and die.

In a mouse model of ALS caused by mutated UBQLN2, the researchers found that decreasing levels of either of these enzymes could reduce nerve cell death, supporting “ILVBL and ALDH3A2 as key effectors mediating mutant UBQLN2-induced neurodegeneration,” they wrote.

The scientists then explored whether this mechanism also plays a role in ALS cases where UBQLN2 is not mutated. In almost all ALS patients, the TDP-43 protein forms abnormal clumps in nerve cells, and the researchers found that healthy UBQLN2 protein can get stuck in these clumps. This stops it from regulating ILVBL and ALDH3A2, leading to dysregulation of lipid levels and, consequently, nerve cell damage and death. Decreasing levels of ILVBL or ALDH3A2 helped improve nerve cell survival in the presence of TDP-43 clumps.

“Our findings demonstrate that TDP-43 [protein clumping] compromises the ability of UBQLN2 to regulate ILVBL and ALDH3A2 turnover,” the scientists wrote. “This disruption may underlie key neurodegenerative features” in ALS and other diseases, they said.