Prolyl oligopeptidase acts as a link between chaperone-mediated autophagy and macroautophagy

The accumulation of aggregated alpha-synuclein (alpha-syn) has been identified as the primary component of Lewy bodies that are the pathological hallmarks of Parkinson's disease (PD). Several preclinical studies have shown alpha-syn aggregation, and particularly the intermediates formed during the aggregation process to be toxic to cells. Current PD treatments only provide symptomatic relief, and alpha-syn serves as a promising target to develop a disease-modifying therapy for PD. Our previous studies have revealed that a small-molecular inhibitor for prolyl oligopeptidase (PREP), KYP-2047, increases alpha-syn degradation by accelerating macroautophagy (MA) leading to disease-modifying effects in preclinical PD models. However, alpha-syn is also degraded by chaperone-mediated autophagy (CMA). In the present study, we tested the effects of PREP inhibition or deletion on CMA activa-tion and alpha-syn degradation. HEK-293 cells were transfected with alpha-syn and incubated with 1 & 10 mu M KYP-2047 for 24 h. Both 1 & 10 mu M KYP-2047 increased LAMP-2A levels, induced alpha-syn degradation and reduced the expression of Hsc70, suggesting that the PREP inhibitor prevented alpha-syn aggregation by activating the CMA pathway. Similarly, KYP-2047 increased the LAMP-2A immunoreactivity and reduced the Hsc70 levels in mouse primary cortical neurons. When LAMP-2A was silenced by a siRNA, KYP-2047 increased the LC3BII/LC3BI ratio and accelerated the clearance of alpha-syn. Additionally, KYP-2047 induced CMA effectively also when MA was blocked by bafilomycin A1. Based on our results, we suggest that PREP might function as a core network node in MA-CMA crosstalk, and PREP inhibition can reduce alpha-syn levels via both main autophagy systems.

Automated summary

Previous studies have shown that the PREP inhibitor KYP-2047 can promote the degradation of alpha-syn through the activation of the CMA pathway, leading to disease-modifying effects in PD treatment.