Prolyl oligopeptidase inhibition activates autophagy via protein phosphatase 2A

Reinis Svarcbahs, Maria Jäntti, Tommi Kilpeläinen, Ulrika H. Julku, Lauri Urvas, Saara Kivioja, Susanna Norrbacka, Timo T. Myöhänen

Research output: Contribution to journalArticleScientificpeer-review

31 Citations (Scopus)

Abstract

Prolyl 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 increased PP2A activity, leading to activation of death-associated 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.

Original languageEnglish
Article number104558
Pages (from-to)104558
JournalPharmacological Research
Volume151
DOIs
Publication statusPublished - Jan 2020
MoE publication typeA1 Journal article-refereed

Keywords

  • Alzheimer's disease
  • Bafilomycin A1 (PubChem CID: 6436223)
  • FTY-720 (fingolimod, PubChem CID: 107970)
  • KYP-2047 (PubChem CID: 11198569)
  • Neurodegeneration
  • Okadaic acid (PubChem CID: 446512)
  • Parkinson's disease
  • PP242 (PubChem CID: 135565635)
  • Protein phosphatase 2 phosphatase activator
  • Protein phosphatase methylesterase 1
  • Rapamycin (sirolimus, PubChem CID: 5284616)
  • Serine protease
  • Parkinson Disease/drug therapy
  • Humans
  • Autophagy/drug effects
  • Male
  • Enzyme Inhibitors/pharmacology
  • Gene Deletion
  • HEK293 Cells
  • Cell Line
  • Mice, Inbred C57BL
  • Prolyl Oligopeptidases/antagonists & inhibitors
  • Mice, Knockout
  • Protein Phosphatase 2/metabolism
  • Animals

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