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

H. Cui, S. Norrbacka, T. T. Myöhänen (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

6 Citations (Scopus)

Abstract

The accumulation of aggregated α-synuclein (α-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 α-syn aggregation, and particularly the intermediates formed during the aggregation process to be toxic to cells. Current PD treatments only provide symptomatic relief, and α-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 α-syn degradation by accelerating macroautophagy (MA) leading to disease-modifying effects in preclinical PD models. However, α-syn is also degraded by chaperone-mediated autophagy (CMA). In the present study, we tested the effects of PREP inhibition or deletion on CMA activation and α-syn degradation. HEK-293 cells were transfected with α-syn and incubated with 1 & 10 µM KYP-2047 for 24 h. Both 1 & 10 µM KYP-2047 increased LAMP-2A levels, induced α-syn degradation and reduced the expression of Hsc70, suggesting that the PREP inhibitor prevented α-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 α-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 α-syn levels via both main autophagy systems.

Original languageEnglish
Article number114899
Pages (from-to)114899
JournalBiochemical Pharmacology
Volume197
DOIs
Publication statusPublished - Mar 2022
MoE publication typeA1 Journal article-refereed

Keywords

  • Chaperone-mediated autophagy
  • Macroautophagy
  • Neurodegeneration
  • Parkinson's disease
  • Prolyl oligopeptidase inhibition
  • α-synuclein

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