Abstract Proteasome is the principal hydrolytic machinery responsible for the great majority of protein degradation. The past three decades have testified prominent advances about proteasome involved in almost every aspect of biological processes. Nonetheless, inappropriate increase or decrease in proteasome function is regarded as a causative factor in several diseases. Proteasome abundance and proper assembly need to be precisely controlled. Indeed, various neurodegenerative diseases including Parkinson’s disease (PD) share a common pathological feature, intracellular protein accumulation such as α-synuclein. Proteasome activation may effectively remove aggregates and prevent the neurodegeneration in PD, which provides a potential application for disease-modifying treatment. In this review, we build on the valuable discoveries related to different types of proteolysis by distinct forms of proteasome, and how its regulatory and catalytic particles promote protein elimination. Additionally, we summarize the emerging ideas on the proteasome homeostasis regulation by targeting transcriptional, translational, and post-translational levels. Given the imbalanced proteostasis in PD, the strategies for intensifying proteasomal degradation are advocated as a promising approach for PD clinical intervention.
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