Hyperactive 20S Proteasome Enhances Proteostasis and ERAD in <i>C. elegans</i> via degradation of Intrinsically Disordered Proteins.

ABSTRACT: Age-related proteinopathies, including Alzheimer's and Parkinson's disease, are driven by the toxic accumulation of misfolded proteins, particularly intrinsically disordered proteins (IDPs), that overwhelm cellular proteostasis. The proteasome is responsible for the clearance of these proteins, but it is unclear why it fails to do so in these diseases. Here, we report a novel strategy employing a C. elegans model with a hyperactive 20S proteasome (α3ΔN) to achieve selective activation. This activation robustly enhances the degradation of IDPs and misfolded proteins, markedly reduces oxidative damage, and significantly improves ER-associated degradation (ERAD). Notably, aggregation-prone substrates, such as endogenous vitellogenins and human alpha-1 antitrypsin (ATZ), are efficiently

SUBMITTER: Salcedo-Tacuma D 

PROVIDER: S-EPMC11014606 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature