The effect of prolyl oligopeptidase inhibitors on alpha-synuclein aggregation and autophagy cannot be predicted by their inhibitory efficacy

Show simple item record Kilpeläinen, Tommi P. Hellinen, Laura Vrijdag, Johannes Yan, Xu Svarcbahs, Reinis Vellonen, Kati-Sisko Lambeir, Anne-Marie Huttunen, Henri Urtti, Arto Wallen, Erik A. A. Myohanen, Timo T. 2020-09-10T13:06:01Z 2020-09-10T13:06:01Z 2020-08
dc.identifier.citation Kilpeläinen , T P , Hellinen , L , Vrijdag , J , Yan , X , Svarcbahs , R , Vellonen , K-S , Lambeir , A-M , Huttunen , H , Urtti , A , Wallen , E A A & Myohanen , T T 2020 , ' The effect of prolyl oligopeptidase inhibitors on alpha-synuclein aggregation and autophagy cannot be predicted by their inhibitory efficacy ' , Biomedicine & Pharmacotherapy , vol. 128 , 110253 .
dc.identifier.other PURE: 144256193
dc.identifier.other PURE UUID: 932c6bbd-839d-49a9-801f-9283249af904
dc.identifier.other WOS: 000561740400016
dc.identifier.other ORCID: /0000-0002-9867-4438/work/80218095
dc.identifier.other ORCID: /0000-0002-9277-6687/work/80224224
dc.identifier.other ORCID: /0000-0002-1312-9837/work/80226291
dc.description.abstract Previous studies have shown that prolyl oligopeptidase (PREP) negatively regulates autophagy and increases the aggregation of alpha-synuclein (alpha Syn), linking it to the pathophysiology of Parkinson's disease. Our earlier results have revealed that the potent small molecular PREP inhibitor KYP-2047 is able to increase autophagy and decrease dimerization of alpha Syn but other PREP inhibitors have not been systematically studied for these two protein-protein interaction mediated biological functions of PREP. In this study, we characterized these effects for 12 known PREP inhibitors with IC50-values ranging from 0.2 nM to 1010 nM. We used protein-fragment complementation assay (PCA) to assess alpha Syn dimerization and Western Blot of microtubule-associated protein light chain 3B II (LC3B-II) and a GFP-LC3-RFP expressing cell line to study autophagy. In addition, we tested selected compounds in a cell-free alpha Syn aggregation assay, native gel electrophoresis, and determined the compound concentration inside the cell by LC-MS. We found that inhibition of the proteolytic activity of PREP did not predict decreased alpha Syn dimerization or increased autophagy, and we also confirmed that this result did not simply reflect concentration differences of the compounds inside the cell. Thus, PREP ligands regulate the effect of PREP on autophagy and alpha Syn aggregation through a conformational stabilization of the enzyme that is not equivalent to inhibiting its proteolytic activity. en
dc.format.extent 10
dc.language.iso eng
dc.relation.ispartof Biomedicine & Pharmacotherapy
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject Serine protease
dc.subject Alpha-Synuclein
dc.subject Autophagy
dc.subject Parkinson's disease
dc.subject Protein conformation
dc.subject ACTIVE-SITE
dc.subject CELL
dc.subject KYP-2047
dc.subject PROTEIN
dc.subject BRAIN
dc.subject PROLINE
dc.subject 317 Pharmacy
dc.title The effect of prolyl oligopeptidase inhibitors on alpha-synuclein aggregation and autophagy cannot be predicted by their inhibitory efficacy en
dc.type Article
dc.contributor.organization PREP in neurodegenerative disorders
dc.contributor.organization Division of Pharmacology and Pharmacotherapy
dc.contributor.organization Drug Research Program
dc.contributor.organization Neuroscience Center
dc.contributor.organization Regenerative pharmacology group
dc.contributor.organization Henri Juhani Huttunen / Principal Investigator
dc.contributor.organization Drug Delivery Unit
dc.contributor.organization Division of Pharmaceutical Biosciences
dc.contributor.organization Division of Pharmaceutical Chemistry and Technology
dc.contributor.organization Pharmaceutical Design and Discovery group
dc.contributor.organization Erik Wallen / Principal Investigator
dc.contributor.organization Faculty of Pharmacy
dc.contributor.organization Divisions of Faculty of Pharmacy
dc.description.reviewstatus Peer reviewed
dc.relation.issn 0753-3322
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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