Prolyl oligopeptidase inhibition by KYP-2407 increases alpha-synuclein fibril degradation in neuron-like cells

Show simple item record Rostami, Jinar Jäntti, Maria Cui, Hengjing Rinne, Maiju K. Kukkonen, Jyrki P. Falk, Anna Erlandsson, Anna Myöhänen, Timo 2020-12-10T12:56:02Z 2020-12-10T12:56:02Z 2020-11
dc.identifier.citation Rostami , J , Jäntti , M , Cui , H , Rinne , M K , Kukkonen , J P , Falk , A , Erlandsson , A & Myöhänen , T 2020 , ' Prolyl oligopeptidase inhibition by KYP-2407 increases alpha-synuclein fibril degradation in neuron-like cells ' , Biomedicine & Pharmacotherapy , vol. 131 , 110788 .
dc.identifier.other PURE: 157190542
dc.identifier.other PURE UUID: 585a73bf-25f9-45c1-ad75-2c6268e8f9e0
dc.identifier.other WOS: 000582699600144
dc.identifier.other ORCID: /0000-0002-6989-1564/work/85117285
dc.identifier.other ORCID: /0000-0002-9277-6687/work/85118218
dc.identifier.other ORCID: /0000-0003-3218-2841/work/85118605
dc.description Corrigendum: Biomedicine & Pharmacotherapy 133 (2021) 111019 WOS:000604603600003
dc.description.abstract Growing evidence emphasizes insufficient clearance of pathological alpha-synuclein (alpha SYN) aggregates in the progression of Parkinson's disease (PD). Consequently, cellular degradation pathways represent a potential therapeutic target. Prolyl oligopeptidase (PREP) is highly expressed in the brain and has been suggested to increase alpha SYN aggregation and negatively regulate the autophagy pathway. Inhibition of PREP with a small molecule inhibitor, KYP-2407, stimulates autophagy and reduces the oligomeric species of alpha SYN aggregates in PD mouse models. However, whether PREP inhibition has any effects on intracellular alpha SYN fibrils has not been studied before. In this study, the effect of KYP2407 on alpha SYN preformed fibrils (PFFs) was tested in SH-SY5Y cells and human astmcytes. Immunostaining analysis revealed that both cell types accumulated alpha SYN PFFs intracellularly but KYP-2047 decreased intracellular alpha SYN deposits only in SH-SY5Y cells, as astrocytes did not show any PREP activity. Western blot analysis confirmed the reduction of high molecular weight alpha SYN species in SH-SY5Y cell lysates, and secretion of aSYN from SH-SY5Y cells also decreased in the presence of KYP-2407. Accumulation of alpha SYN inside the SH-SY5Y cells resulted in an increase of the auto-lysosomal proteins p62 and LC3BII, as well as calpain 1 and 2, which have been shown to be associated with PD pathology. Notably, treatment with KYP-2407 significantly reduced p62 and LC3BII levels, indicating an increased autophagic flux, and calpain 1 and 2 levels returned to normal in the presence of KYP-2407. Our findings indicate that PREP inhibition can potentially be used as therapy to reduce the insoluble intracellular alpha SYN aggregates. en
dc.format.extent 10
dc.language.iso eng
dc.relation.ispartof Biomedicine & Pharmacotherapy
dc.rights cc_by
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject Autophagy
dc.subject Alpha-synuclein
dc.subject Fibrils
dc.subject Propagation
dc.subject Calpain
dc.subject Synucleinopathies
dc.subject Neurodegeneration
dc.subject LEWY BODIES
dc.subject ASTROCYTES
dc.subject AUTOPHAGY
dc.subject PATHOLOGY
dc.subject CLEAVAGE
dc.subject CALPAIN
dc.subject 317 Pharmacy
dc.title Prolyl oligopeptidase inhibition by KYP-2407 increases alpha-synuclein fibril degradation in neuron-like cells 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 Division of Pharmaceutical Chemistry and Technology
dc.contributor.organization Department of Pharmacology
dc.contributor.organization Medicum
dc.contributor.organization Faculty of Pharmacy
dc.contributor.organization Regenerative pharmacology group
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
dc.type.version publishedVersion

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