Prolyl oligopeptidase inhibition activates autophagy via protein phosphatase 2A

Publication date: Available online 20 November 2019Source: Pharmacological ResearchAuthor(s): Reinis Svarcbahs, Maria Jäntti, Tommi Kilpeläinen, Ulrika H. Julku, Lauri Urvas, Saara Kivioja, Susanna Norrbacka, Timo T. MyöhänenAbstractProlyl oligopeptidase (PREP) is a serine protease that has been studied particularly in the context of neurodegenerative diseases for decades but its physiological function has remained unclear. We have previously found that PREP negatively regulates beclin1-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 increas...
Source: Pharmacological Research - Category: Drugs & Pharmacology Source Type: research