Prolyl oligopeptidase inhibition activates autophagy via protein phosphatase 2A

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Svarcbahs , R , Jäntti , M , Kilpeläinen , T , Julku , U , Urvas , L , Kivioja , S , Norrbacka , S & Myöhänen , T 2020 , ' Prolyl oligopeptidase inhibition activates autophagy via protein phosphatase 2A ' , Pharmacological Research , vol. 151 , 104558 .

Title: Prolyl oligopeptidase inhibition activates autophagy via protein phosphatase 2A
Author: Svarcbahs, Reinis; Jäntti, Maria; Kilpeläinen, Tommi; Julku, Ulrika; Urvas, Lauri; Kivioja, Saara; Norrbacka, Susanna; Myöhänen, Timo
Contributor organization: Regenerative pharmacology group
PREP in neurodegenerative disorders
Division of Pharmacology and Pharmacotherapy
Drug Research Program
Divisions of Faculty of Pharmacy
University of Helsinki
Faculty of Pharmacy
University Management
Date: 2020-01
Language: eng
Number of pages: 16
Belongs to series: Pharmacological Research
ISSN: 1043-6618
Abstract: Prolyl oligopeptidase (PREP) is a serine protease that has been studied particularly in the context of neurode-generative diseases for decades but its physiological function has remained unclear. We have previously found that PREP negatively regulates beclinl-mediated macroautophagy (autophagy), and that PREP inhibition by a small-molecule inhibitor induces clearance of protein aggregates in Parkinson's disease models. Since autophagy induction has been suggested as a potential therapy for several diseases, we wanted to further characterize how PREP regulates autophagy. We measured the levels of various kinases and proteins regulating beclin1-autophagy in HEK-293 and SH-SY5Y cell cultures after PREP inhibition, PREP deletion, and PREP overexpression and restoration, and verified the results in vivo by using PREP knock-out and wild-type mouse tissue where PREP was restored or overexpressed, respectively. We found that PREP regulates autophagy by interacting with protein phosphatase 2A (PP2A) and its endogenous inhibitor, protein phosphatase methylesterase 1 (PME1), and activator (protein phosphatase 2 phosphatase activator, PTPA), thus adjusting its activity and the levels of PP2A in the intracellular pool. PREP inhibition and deletion increased PP2A activity, leading to activation of deathassociated protein kinase 1 (DAPK1), beclin1 phosphorylation and induced autophagy while PREP overexpression reduced this. Lowered activity of PP2A is connected to several neurodegenerative disorders and cancers, and PP2A activators would have enormous potential as drug therapy but development of such compounds has been a challenge. The concept of PREP inhibition has been proved safe, and therefore, our study supports the further development of PREP inhibitors as PP2A activators.
Alzheimer's disease
Parkinson's disease
Protein phosphatase 2 phosphatase activator
Protein phosphatase methylesterase 1
Serine protease
317 Pharmacy
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: acceptedVersion

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