title: Prolyl Oligopeptidase Regulates Dopamine Transporter Phosphorylation in the Nigrostriatal Pathway of Mouse.
abstract: Alpha-synuclein is the main component of Lewy bodies, a histopathological finding of Parkinson's disease. Prolyl oligopeptidase (PREP) is a serine protease that binds to α-synuclein and accelerates its aggregation in vitro. PREP enzyme inhibitors have been shown to block the α-synuclein aggregation process in vitro and in cellular models, and also to enhance the clearance of α-synuclein aggregates in transgenic mouse models. Moreover, PREP inhibitors have induced alterations in dopamine and metabolite levels, and dopamine transporter immunoreactivity in the nigrostriatal tissue. In this study, we characterized the role of PREP in the nigrostriatal dopaminergic and GABAergic systems of wild-type C57Bl/6 and PREP knockout mice, and the effects of PREP overexpression on these systems. Extracellular concentrations of dopamine and protein levels of phosphorylated dopamine transporter were increased and dopamine reuptake was decreased in the striatum of PREP knockout mice, suggesting increased internalization of dopamine transporter from the presynaptic membrane. Furthermore, PREP overexpression increased the level of dopamine transporters in the nigrostriatal tissue but decreased phosphorylated dopamine transporters in the striatum in wild-type mice. Our results suggest that PREP regulates the function of dopamine transporter, possibly by controlling the phosphorylation and transport of dopamine transporter into the striatum or synaptic membrane.
authors.affiliation: Division of Pharmacology and Pharmacotherapy, University of Helsinki, Viikinkaari 5E, P.O. Box 56, 00014, Helsinki, Finland.
authors.forename: Ulrika H
authors.initials: UH
authors.lastname: Julku
authors.affiliation: Institute of Biotechnology, University of Helsinki, Viikinkaari 5D, P.O. Box 56, 00014, Helsinki, Finland.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Panhelainen
authors.affiliation: Division of Pharmacology and Pharmacotherapy, University of Helsinki, Viikinkaari 5E, P.O. Box 56, 00014, Helsinki, Finland.
authors.forename: Saija E
authors.initials: SE
authors.lastname: Tiilikainen
authors.affiliation: Division of Pharmacology and Pharmacotherapy, University of Helsinki, Viikinkaari 5E, P.O. Box 56, 00014, Helsinki, Finland.
authors.forename: Reinis
authors.initials: R
authors.lastname: Svarcbahs
authors.affiliation: Division of Pharmacology and Pharmacotherapy, University of Helsinki, Viikinkaari 5E, P.O. Box 56, 00014, Helsinki, Finland.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Tammimäki
authors.affiliation: Division of Pharmacology and Pharmacotherapy, University of Helsinki, Viikinkaari 5E, P.O. Box 56, 00014, Helsinki, Finland.
authors.forename: T Petteri
authors.initials: TP
authors.lastname: Piepponen
authors.affiliation: Division of Pharmacology and Pharmacotherapy, University of Helsinki, Viikinkaari 5E, P.O. Box 56, 00014, Helsinki, Finland.
authors.forename: Mari H
authors.initials: MH
authors.lastname: Savolainen
authors.affiliation: Division of Pharmacology and Pharmacotherapy, University of Helsinki, Viikinkaari 5E, P.O. Box 56, 00014, Helsinki, Finland. timo.myohanen@helsinki.fi.
authors.forename: Timo T
authors.initials: TT
authors.lastname: Myöhänen
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D055442:Metabolome; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D000085822:Prolyl Oligopeptidases; D012697:Serine Endopeptidases / Q000172:deficiency / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; C493215:Slc6a3 protein, mouse; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases; D004298:Dopamine
keywords: DAT; Dopamine; Dopamine transporter; Microdialysis; PREP; Prolyl oligopeptidase