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.

Brief Summary of Results: Hyperactivation of the 20S proteasome resulted in enhanced protein synthesis, extensive proteomic and transcriptomic rewiring, improved oxidative stress defenses, accelerated lipid metabolism, and increased peroxisome proliferation. It also facilitated the ER-associated degradation of proteins prone to aggregation such as ATZ linked to Alpha- antitrypsin deficiency a rare genetic disorder that affects lungs and liver.

Brief Conclusion: Our study highlights a novel role for 20S proteasome hyperactivation in improving proteostasis and lipid metabolism, which may contribute to the longevity and stress resistance observed in the mutant C. elegans. These findings suggest potential therapeutic applications for proteasome activation in addressing proteostasis-related disorders.

For more detailed insights, you can access the full study in the Pre-print.

David Smith Lab at WVU.