Blm10/PA200-activated 20S proteasomes promote α-synuclein degradation and bypass proteasome inhibition in Parkinson disease models

Protein homeostasis is essential for maintaining normal cellular function. However, protein homeostasis efficiency declines with age, leading to the accumulation of aberrant protein structures associated with neurodegenerative diseases such as Parkinsons disease (PD). PD is characterized by the aggregation of alpha-synuclein (Syn) into cytoplasmic inclusions. This process is accompanied by elevated phosphorylation at serine 129 (S129). The accumulation of Syn into aggregates and their propagation disrupts key proteostasis pathways, including the ubiquitin-proteasome system (UPS) or autophagy, contributing to cellular dysfunction and neuronal death. This study identified the proteasome activator Blm10 and its human ortholog PA200 as modulators of Syn degradation and toxicity. The conserved Blm10/PA200 protein plays a key role in regulating proteasome activity and assembly. The Syn expression increases Blm10 protein stability through autophagy inhibition, in a manner dependent on Syn phosphorylation at S129 in yeast. Overexpression of BLM10 or PA200 reduces Syn aggregation and enhances Syn turnover via activation of the 20S proteasome in yeast and mammalian cells. Blm10 and PA200-capped 20S proteasomes efficiently degrade both monomeric as well as oligomeric Syn in vitro. Notably, capped proteasomes retain proteolytic activities in presence of Syn, indicating resistance to Syn-induced inhibition, in contrast to 20S or 26S proteasomes. These results reveal a distinct proteasome subtype that bypasses UPS impairment and restores proteolytic capacity under proteotoxic stress. Our findings establish Blm10/PA200 as critical regulator of Syn proteostasis and highlight its protective role in maintaining protein homeostasis and cell viability under conditions of Syn toxicity.