EPS8 protein drives Huntington's and ALS protein clumps, study finds

A protein pathway that becomes more active with age has been identified as a trigger for the harmful protein clumps seen in Huntington’s disease and amyotrophic lateral sclerosis, according to a study published in Nature Aging on August 3, 2026. Researchers led by Professor Dr. David Vilchez at the CECAD Cluster of Excellence for Aging Research found that the aging-associated protein EPS8 drives neurodegeneration through a specific signaling route.

The discovery affects the millions of people worldwide who develop neurodegenerative conditions, for which aging is the strongest known risk factor. By pinpointing a molecular link between growing older and disease, the work opens the door to treatments that could slow or stop these currently incurable disorders.

The team used the nematode worm Caenorhabditis elegans to show that EPS8 accumulates with age and hyperactivates RAC signaling, which in turn promotes the buildup of toxic protein aggregates and loss of neuronal function. When the scientists reduced EPS8 activity, the aggregates no longer formed as readily and neuron health was preserved in worm models of both Huntington’s disease and ALS.

The study, titled “The aging factor EPS8 induces disease-related protein aggregation through RAC signaling hyperactivation,” also tested human cell models. Lowering EPS8 levels in these cells prevented the accumulation of toxic protein clumps, demonstrating that the mechanism is conserved across species. First author Dr. Seda Koyuncu said the findings may help fill a gap in understanding how age-related changes contribute to different neurodegenerative diseases.

Previous research had shown that EPS8 builds up as worms age and triggers damaging stress responses that shorten lifespan. The new work builds on that by directly connecting EPS8 to the pathological hallmarks of Huntington’s and ALS. The signaling molecules involved have been preserved throughout evolution, making the worm a useful model for human disease.

The results point to EPS8 and its signaling partners as potential targets for future therapies. While scientists do not yet know exactly how increased EPS8 activity causes protein aggregation, the study identifies a direct molecular connection between aging and neurodegeneration that could guide drug development.