A protein called EPS8, better known for helping cells build finger-like surface projections, appears to have a second job that only shows up with age: switching on the kind of toxic protein clumping seen in amyotrophic lateral sclerosis (ALS) and Huntington’s disease. That is the central finding of a new study from researchers at the CECAD Cluster of Excellence for Aging Research at the University of Cologne, published in Nature Aging.
What the researchers found
The team, led by Professor David Vilchez with first author Dr. Seda Koyuncu, reports that EPS8 levels rise with age and, together with RAC signaling, drive pathological protein aggregation. They demonstrated the effect in C. elegans (roundworm) models of Huntington’s disease and ALS, and traced the same mechanism into human cell models of both diseases.
Critically, the relationship ran in both directions: when the researchers reduced EPS8 activity, harmful protein aggregates were prevented and nerve cell function was preserved. That reversibility is what makes the finding more than a descriptive observation — it points to EPS8 and its downstream signaling as a plausible target for future intervention, not just a marker of disease.
Why aging is the missing link
Age is the single strongest known risk factor for neurodegenerative disease, but the molecular reason a decades-long aging process converts into disease onset within a comparatively short window has been hard to pin down. “For years, we’ve known that age is the major common risk factor for different neurodegenerative diseases,” said Dr. Koyuncu, the study’s first author, of the gap this research addresses.
By identifying a specific protein whose age-related accumulation actively drives aggregation — rather than simply correlating with it — the study offers a candidate mechanistic bridge between generic cellular aging and the specific pathology of diseases like ALS and Huntington’s. Both conditions are defined by the buildup of misfolded, aggregation-prone proteins that overwhelm a cell’s normal quality-control systems; showing that an aging-linked protein can actively trigger that buildup, and that dialing it back reverses the effect in model systems, is a meaningfully different kind of evidence than an association study.
What this does and doesn’t mean yet
The core experiments were carried out in worm models, with the mechanism further supported in human cell models — an important step beyond invertebrate biology, but still short of validation in intact human tissue, animal models with more complex nervous systems, or patients. As with any single mechanistic study, EPS8 hyperactivation is very unlikely to be the sole driver of ALS or Huntington’s pathology; both diseases have multiple contributing genetic and cellular factors. What the findings do establish is a specific, testable molecular pathway — age-driven EPS8/RAC signaling — that other labs can now probe, replicate, and attempt to target therapeutically.
Source
Koyuncu, S., Vilchez, D., et al. “The aging factor EPS8 induces disease-related protein aggregation.” Nature Aging (2025). https://www.nature.com/articles/s43587-025-00943-w. Coverage summarized from the University of Cologne’s CECAD Cluster of Excellence for Aging Research and independent science-press reporting.
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