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

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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 . https://doi.org/10.1016/j.biopha.2020.110788

Title: Prolyl oligopeptidase inhibition by KYP-2407 increases alpha-synuclein fibril degradation in neuron-like cells
Author: Rostami, Jinar; Jäntti, Maria; Cui, Hengjing; Rinne, Maiju K.; Kukkonen, Jyrki P.; Falk, Anna; Erlandsson, Anna; Myöhänen, Timo
Contributor: University of Helsinki, PREP in neurodegenerative disorders
University of Helsinki, Division of Pharmacology and Pharmacotherapy
University of Helsinki, Division of Pharmaceutical Chemistry and Technology
University of Helsinki, Department of Pharmacology
University of Helsinki, Faculty of Pharmacy
Date: 2020-11
Language: eng
Number of pages: 10
Belongs to series: Biomedicine & Pharmacotherapy
ISSN: 0753-3322
URI: http://hdl.handle.net/10138/322668
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.
Subject: Autophagy
Alpha-synuclein
Fibrils
Propagation
Calpain
Synucleinopathies
Neurodegeneration
PARKINSONS-DISEASE
FILAMENTOUS INCLUSIONS
PROTEIN-LEVELS
LEWY BODIES
ASTROCYTES
AUTOPHAGY
ENDOPEPTIDASE
PATHOLOGY
CLEAVAGE
CALPAIN
317 Pharmacy
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