Title
A prolyl oligopeptidase inhibitor, KYP-2047, reduces <tex>$\alpha$</tex>-synuclein protein levels and aggregates in cellular and animal models of Parkinson's disease
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Publication type
article
Publication
London ,
Subject
Biology
Pharmacology. Therapy
Source (journal)
British journal of pharmacology. - London
Volume/pages
166(2012) :3 , p. 1097-1113
ISSN
0007-1188
ISI
000303923000023
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
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.
Full text (open access)
https://repository.uantwerpen.be/docman/irua/ab372f/2032.pdf
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