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Cui H, Norrbacka S, Myöhänen TT. Prolyl oligopeptidase acts as a link between chaperone-mediated autophagy and macroautophagy. Biochem Pharmacol. 2021;197:114899doi: 10.1016/j.bcp.2021.114899.
Cui, H., Norrbacka, S., & Myöhänen, T. T. (2021). Prolyl oligopeptidase acts as a link between chaperone-mediated autophagy and macroautophagy. Biochemical pharmacology, 197114899. https://doi.org/10.1016/j.bcp.2021.114899
Cui, H, et al. "Prolyl oligopeptidase acts as a link between chaperone-mediated autophagy and macroautophagy." Biochemical pharmacology vol. 197 (2021): 114899. doi: https://doi.org/10.1016/j.bcp.2021.114899
Cui H, Norrbacka S, Myöhänen TT. Prolyl oligopeptidase acts as a link between chaperone-mediated autophagy and macroautophagy. Biochem Pharmacol. 2021 Dec 28;197:114899. doi: 10.1016/j.bcp.2021.114899. Epub 2021 Dec 28. PMID: 34968496.
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Biochem Pharmacol. 2021 Dec 28;197:114899. doi: 10.1016/j.bcp.2021.114899. Epub 2021 Dec 28.

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

Biochemical pharmacology

H Cui, S Norrbacka, T T Myöhänen

Affiliations

  1. Division of Pharmacology and Pharmacotherapy/Drug Research Program, University of Helsinki, Finland.
  2. Division of Pharmacology and Pharmacotherapy/Drug Research Program, University of Helsinki, Finland; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland. Electronic address: [email protected].

PMID: 34968496 DOI: 10.1016/j.bcp.2021.114899

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.

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Keywords: Chaperone-mediated autophagy; Macroautophagy; Neurodegeneration; Parkinson’s disease; Prolyl oligopeptidase inhibition; α-synuclein

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