FLI Seminar with Seda Koyuncu

Aging is a major risk factor for neurodegenerative disorders associated with protein aggregation, partly due to a progressive decline in protein homeostasis (proteostasis). One of the central mechanisms that safeguards proteostasis is ubiquitination which regulates protein fate in many ways including degradation via the proteasome. However, how age-related changes in ubiquitin signaling contribute to longevity and neurodegeneration remains poorly understood. To address this, we analyzed age-dependent changes in ubiquitin-proteome in Caenorhabditis elegans, identifying key mechanisms linking ubiquitin dysregulation to aging and age-related neurodegenerative diseases.

Our findings show that aging leads to a profound rewiring of ubiquitination through the entire proteome, primarily driven by increased deubiquitinase activity. These age-dependent alterations disrupt ubiquitin-mediated proteasomal degradation of structural and regulatory proteins including EPS-8 determines longevity. Remarkably, hyperactivation of EPS-8/RAC signaling in neurons and muscle tissue, not only impairs cytoskeletal dynamics but also promotes the aggregation of neurodegenerative disease-associated proteins.

These aggregates further impair cellular function, contributing to age-related neurotoxicity and age-related neurodegeneration. We also identify the deubiquitinating enzyme USP4 as a key regulator of EPS8 ubiquitination and degradation in both worms and human cells.

Our findings suggest that targeting EPS8 and its regulatory mechanisms, such as USP4-mediated degradation, may offer therapeutic strategies for aging and age-related neurodegenerative diseases.

Seda Koyuncu is a Postdoctoral Researcher at CECAD-Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated disease, Cologne.

More information:

Vilchez Lab

The seminar will be held as an in-person event.