Proteasomal hyperactivation as therapeutic target for proteinopathies

Project description: Proteasome Hyperactivation in C. elegans We designed a C. elegans model to investigate the effects of 20S proteasome hyperactivation, specifically through the gate-opening mechanism. The focus is on how this hyperactivation targets intrinsically disordered proteins, influencing various cellular processes.

Key findings

• Selective IDP clearance & faster turnover: Hyperactivation accelerates degradation of intrinsically disordered/misfolded proteins and increases global protein turnover (synthesis + degradation).
• Oxidative stress resilience: Markedly reduces oxidative damage and boosts survival under H₂O₂, t-BuOOH, and juglone. Protection persists even when most SODs are absent (quad-sod background).
• Enhanced ERAD: Post-translational depletion of endogenous vitellogenins (ApoB homologs) and more efficient clearance of pathogenic human ATZ in the intestine; effects depend on the canonical Cdc48/p97 ERAD machinery.
• UPR-independent benefits: Increased ER stress resistance and lifespan extension occur without requiring xbp-1–mediated UPR (BiP/hsp-4).
• Systems-level rewiring: Coordinated proteomic/transcriptomic changes highlight broad remodeling of protein quality control and translation programs.

Brief Conclusion: Constitutive 20S gate opening defines a potent, IDP-targeted proteostasis pathway that mitigates oxidative and ER proteotoxic stress, extends lifespan, and suggests a therapeutic angle for neurodegenerative diseases and α1-antitrypsin deficiency.

For more detailed insights, you can access the full study in:

• Published article: Science Advances (issue 10, 2025) Sci.adv-link
• Pubmed: link

David Smith Lab at WVU.