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

Biomedicine & Pharmacotherapy

Anna Falk¹  Jyrki P. Kukkonen²  Maiju K. Rinne³  Timo Myöhänen⁴  Maria Jäntti⁴  Hengjing Cui⁴  Jinar Rostami⁵  Anna Erlandsson⁵ 

[1] Department of Neuroscience, Karolinska Institutet, Stockholm, 17177, Sweden;Department of Pharmacology, Institute of Biomedicine, Faculty of Medicine, P.O. Box 63, 00014, University of Helsinki, Finland;Division of Pharmaceutical Chemistry and Technology/Drug Research Program, Faculty of Pharmacy, P.O. Box 56, 00014, University of Helsinki, Finland;Division of Pharmacology and Pharmacotherapy/Drug Research Program, University of Helsinki, Viikinkaari 5E, P.O. Box 56, 00014, University of Helsinki, Finland;Molecular Geriatrics, Department of Public Health and Caring Sciences, Rudbeck Laboratory, Uppsala University, 751 85, Uppsala, Sweden;

关键词: Autophagy;    Alpha-synuclein;    Fibrils;    Propagation;    Calpain;    Synucleinopathies;   

DOI  :  

来源: DOAJ

【 摘 要 】

Growing evidence emphasizes insufficient clearance of pathological alpha-synuclein (αSYN) 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 αSYN 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 αSYN aggregates in PD mouse models. However, whether PREP inhibition has any effects on intracellular αSYN fibrils has not been studied before. In this study, the effect of KYP2407 on αSYN preformed fibrils (PFFs) was tested in SH-SY5Y cells and human astrocytes. Immunostaining analysis revealed that both cell types accumulated αSYN PFFs intracellularly but KYP-2047 decreased intracellular αSYN deposits only in SH-SY5Y cells, as astrocytes did not show any PREP activity. Western blot analysis confirmed the reduction of high molecular weight αSYN species in SH-SY5Y cell lysates, and secretion of αSYN from SH-SY5Y cells also decreased in the presence of KYP-2407. Accumulation of αSYN 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 αSYN aggregates.

【 授权许可】

Unknown