Prolyl oligopeptidase inhibition activates autophagy via protein phosphatase 2A.
Pharmacol Res
; 151: 104558, 2020 01.
Article
en En
| MEDLINE
| ID: mdl-31759088
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.
Palabras clave
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); PP242 (PubChem CID: 135565635); Parkinson's disease; Protein phosphatase 2 phosphatase activator; Protein phosphatase methylesterase 1; Rapamycin (sirolimus, PubChem CID: 5284616); Serine protease
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Autofagia
/
Eliminación de Gen
/
Proteína Fosfatasa 2
/
Prolil Oligopeptidasas
Límite:
Animals
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Humans
/
Male
Idioma:
En
Revista:
Pharmacol Res
Asunto de la revista:
FARMACOLOGIA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Finlandia
Pais de publicación:
Países Bajos