Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Pharmacology & Pharmacy, serine protease, prolyl oligopeptidase inhibitor, a-synuclein, Parkinson's disease, protein aggregation, LEWY BODY DEMENTIA, ENDOPEPTIDASE INHIBITOR, RAT-BRAIN, WILD-TYPE, SUBCELLULAR-LOCALIZATION, FIBRIL FORMATION, TRANSGENIC MICE, SPATIAL MEMORY, IN-VIVO, NEURONS, Animals, Blotting, Western, Brain, Cell Culture Techniques, Cell Line, Tumor, Cell Survival, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Fluorescence, Motor Activity, Oxidative Stress, Parkinsonian Disorders, Proline, Prolyl Oligopeptidases, Reverse Transcriptase Polymerase Chain Reaction, Serine Endopeptidases, Serine Proteinase Inhibitors, Transfection, alpha-Synuclein, 1115 Pharmacology and Pharmaceutical Sciences, 3214 Pharmacology and pharmaceutical sciences

Abstract:

Background and purpose  The aggregation of α-synuclein (α-syn) is connected to the pathology of Parkinson's disease. Recently, it was shown that prolyl oligopeptidase (PREP) accelerates the aggregation of α-syn in vitro. The aim of this study was to investigate the effects of a PREP inhibitor, KYP-2047, on α-syn aggregation in cell lines overexpressing wild-type or A30P/A53T mutant human α-syn, and in the brains of two A30P α-syn transgenic mouse strains. Experimental approach  Cells were exposed to oxidative stress, and then incubated with the PREP inhibitor during or after the stress. Wild-type or transgenic mice were treated for 5 days with KYP-2047 (2x3 mg/kg a day). Besides immunohistochemistry and thioflavin S staining, soluble and insoluble α-syn protein levels were measured by Western blot. α-syn mRNA levels were quantified by PCR. The colocalization of PREP and α-syn, and the effect of KYP-2047 on cell viability were also investigated. Key results  In cell lines, oxidative stress induced a robust aggregation of α-syn, and low concentrations of KYP-2047 significantly reduced the number of cells with α-syn inclusions while abolishing the colocalization of α-syn and PREP. KYP-2047 significantly reduced the amount of aggregated α-syn, and it had beneficial effects on cell viability. In the transgenic mice, a 5-day treatment with the PREP inhibitor reduced the amount of α-syn immunoreactivity and soluble α-syn protein in the brain. Conclusions and implications  The results suggest that the PREP may play a role in brain accumulation and aggregation of α-syn, while KYP-2047 seems to effectively prevent these processes.