title: Inhibition of prolyl oligopeptidase increases the survival of alpha-synuclein overexpressing cells after rotenone exposure by reducing alpha-synuclein oligomers.
abstract: α-Synuclein (aSyn) aggregation, mitochondrial dysfunction and oxidative damage has been shown to be related to the death of dopaminergic neurons in Parkinson's disease (PD). Prolyl oligopeptidase (PREP) is proposed to increase aSyn aggregation, and PREP inhibition has been shown to inhibit the aggregation process in vitro and in vivo. In this study, we investigated the effects of a specific PREP inhibitor, KYP-2047, on rotenone induced aSyn aggregation and increased the production of reactive oxygen species (ROS) in cells overexpressing A53T mutation of aSyn. Rotenone, a mitochondrial toxin that induces oxidative damage and aSyn aggregation, associated with PD pathology, was selected as a model for this study. The results showed that rotenone induced the formation of high-molecular-weight aSyn oligomers, and this was countered by simultaneous incubation with KYP-2047. Inhibition of PREP also decreased the production of ROS in [A53T]aSyn overexpressing cells, leading to improved cell viability.
authors.affiliation: Division of Pharmacology and Toxicology, Faculty of Pharmacy, , Viikinkaari 5E, PO Box 56, FIN-00014 University of Helsinki, Finland. Electronic address: lana.dokleja@helsinki.fi.
authors.forename: Lana
authors.initials: L
authors.lastname: Dokleja
authors.affiliation: Division of Pharmacology and Toxicology, Faculty of Pharmacy, , Viikinkaari 5E, PO Box 56, FIN-00014 University of Helsinki, Finland. Electronic address: mirva.hannula@helsinki.fi.
authors.forename: Mirva J
authors.initials: MJ
authors.lastname: Hannula
authors.affiliation: Division of Pharmacology and Toxicology, Faculty of Pharmacy, , Viikinkaari 5E, PO Box 56, FIN-00014 University of Helsinki, Finland. Electronic address: timo.myohanen@helsinki.fi.
authors.forename: Timo T
authors.initials: TT
authors.lastname: Myöhänen
mesh_terms: D001343:Autophagy; D045744:Cell Line, Tumor; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D000085822:Prolyl Oligopeptidases; D066329:Protein Aggregates; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000633:toxicity*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D012995:Solubility; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: C551540:4-phenylbutanoyl-prolylcyanopyrrolidine; D066329:Protein Aggregates; D017382:Reactive Oxygen Species; D015842:Serine Proteinase Inhibitors; D051844:alpha-Synuclein; D012402:Rotenone; D011392:Proline; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases
keywords: Autophagy; Parkinson's disease; Protein misfolding; Reactive oxygen species; Serine protease