title: The beneficial effect of a prolyl oligopeptidase inhibitor, KYP-2047, on alpha-synuclein clearance and autophagy in A30P transgenic mouse.
abstract: The misfolding and aggregation of α-synuclein (aSyn) eventually lead to an accumulation of toxic forms that disturb normal neuronal function and result in cell death. aSyn rich inclusions are seen in Parkinson's disease, dementia with Lewy bodies and other synucleinopathies. Prolyl oligopeptidase (PREP) can accelerate the aggregation process of aSyn and the inhibition of PREP leads to a decreased amount of aggregated aSyn in cell models and in aSyn transgenic mice. In this study, we investigated the effect of 5- and 28-day PREP inhibitor (KYP-2047) treatments on a mouse strain carrying a point mutation in the aSyn coding gene. Following PREP inhibition, we found a decrease in high molecular-weight oligomeric aSyn and a concomitant increase in the amount of the autophagosome marker, LC3BII, suggesting enhanced macroautophagy (autophagy) and aSyn clearance by KYP-2047. Moreover, 28-day treatment with KYP-2047 caused significant increases in striatal dopamine levels. In cell culture, overexpression of PREP reduced the autophagy. Furthermore, the inhibition of PREP normalized the changes on autophagy markers (LC3BII and p62) caused by an autophagy inhibition or aSyn overexpression, and induced the expression of beclin 1, a positive regulator of autophagy. Taken together, our results suggest that PREP inhibition accelerates the clearance of protein aggregates via increased autophagy and thus normalizes the cell functions in vivo and in vitro. Therefore, PREP inhibition may have future potential in the treatment of synucleinopathies.
authors.affiliation: Division of Pharmacology and Pharmacotherapy, University of Helsinki, 00014, Finland; Optogenetics and Transgenic Technology Core, National Institute of Drug Abuse, Baltimore, MD, USA.
authors.forename: Mari H
authors.initials: MH
authors.lastname: Savolainen
authors.affiliation: Optogenetics and Transgenic Technology Core, National Institute of Drug Abuse, Baltimore, MD, USA.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Richie
authors.affiliation: Optogenetics and Transgenic Technology Core, National Institute of Drug Abuse, Baltimore, MD, USA.
authors.forename: Brandon K
authors.initials: BK
authors.lastname: Harvey
authors.affiliation: Division of Pharmacology and Pharmacotherapy, University of Helsinki, 00014, Finland.
authors.forename: Pekka T
authors.initials: PT
authors.lastname: Männistö
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Maguire-Zeiss
authors.affiliation: Division of Pharmacology and Pharmacotherapy, University of Helsinki, 00014, Finland; Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA. Electronic address: timo.myohanen@helsinki.fi.
authors.forename: Timo T
authors.initials: TT
authors.lastname: Myöhänen
mesh_terms: D000409:Alanine / Q000235:genetics; D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001927:Brain Diseases / Q000188:drug therapy / Q000235:genetics*; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics; D011392:Proline / Q000031:analogs & derivatives* / Q000235:genetics / Q000627:therapeutic use; D000085822:Prolyl Oligopeptidases; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D013997:Time Factors; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: C551540:4-phenylbutanoyl-prolylcyanopyrrolidine; D015842:Serine Proteinase Inhibitors; C497605:Snca protein, mouse; D051844:alpha-Synuclein; D011392:Proline; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases; D000409:Alanine
keywords: Autophagy; Dementia with Lewy bodies; Parkinson's disease; Protein misfolding; Serine protease; Synucleinopathies; Synucleins
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