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Area of Science:

  • Neuroscience
  • Aging Research
  • Molecular Biology

Background:

  • Aging is a primary risk factor for neurodegenerative diseases like Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS).
  • These diseases are characterized by the pathological aggregation of specific proteins.
  • Shared late onset suggests common aging-related mechanisms underlie diverse protein aggregation disorders.

Purpose of the Study:

  • To investigate the role of aging-associated signaling pathways in protein aggregation relevant to neurodegenerative diseases.
  • To identify molecular targets for therapeutic intervention in age-related neurodegeneration.

Main Methods:

  • Utilized Caenorhabditis elegans models to study age-associated EPS8/RAC signaling.
  • Examined the impact of modulating EPS8/RAC signaling on aggregation of HD-related polyglutamine repeats and ALS-related FUS/TDP-43 variants.
  • Employed human cell models to validate findings on EPS8 signaling inhibition.
  • Identified USP4 (deubiquitinating enzyme) as a regulator of EPS8 degradation.

Main Results:

  • Age-associated hyperactivation of EPS8/RAC signaling in worms promotes pathological protein aggregation and neuronal dysfunction.
  • Knockdown of eps-8 or RAC orthologs prevents aggregation and preserves neuronal function during aging.
  • Inhibition of EPS8 signaling reduces protein aggregation and neurodegeneration in human cells.
  • USP4 regulates EPS8 ubiquitination and degradation; reducing USP4 upregulation during aging mitigates EPS-8 accumulation and extends lifespan.

Conclusions:

  • EPS8/RAC signaling is a key driver of age-related protein aggregation and neurodegeneration.
  • Targeting EPS8 signaling and its regulator USP4 presents a promising therapeutic strategy for age-related neurodegenerative diseases.