Study Identifies EPS8’s Role in Driving Neurodegeneration Through Aging

Aging has long been recognized as the primary risk factor for neurodegenerative diseases, but the exact molecular changes that trigger disease development remain uncertain. A research team led by David Vilchez at the University of Cologne sought to better understand this connection. Their work, published in Nature Aging focused on the aging-associated protein EPS8 and the signaling pathways it regulates.

EPS8 naturally accumulates with age and has been associated with harmful stress responses that shorten lifespan in worms. The researchers discovered that increased EPS8 levels, together with activation of its signaling network, drive protein aggregation and neurodegeneration in Caenorhabditis elegans. These processes are hallmark features of age-related diseases such as Huntington’s disease and amyotrophic lateral sclerosis (ALS). Remarkably, by reducing EPS8 activity, they were able to prevent the formation of toxic protein clusters and preserve nerve cell function in worm models of both Huntington’s and ALS.

First author Seda Koyuncu explained: “We are delighted to uncover a molecular mechanism that could shed light on to how aging contributes to diseases like ALS and Huntington’s. For years, we’ve known that age is the major common risk factor for different neurodegenerative diseases. However, how exactly age-related changes contribute to these diseases remain largely unknown. This study may contribute to fill in a part of that puzzle.”

The team also tested whether these insights applied beyond worms. Since EPS8 and its signaling partners are evolutionarily conserved, they are also present in human cells. In human cell models of Huntington’s and ALS, the researchers were able to prevent the build-up of toxic proteins by lowering EPS8 levels, mirroring their results in the worms. Professor Vilchez emphasized the value of these findings: “It’s incredibly exciting that the mechanisms we uncovered in C. elegans are also conserved in human cell models,” highlighting how simple model organisms can reveal mechanisms relevant to human disease.