Myohanen_2012_Br.J.Pharmacol_166_1097

BACKGROUND AND PURPOSE: The aggregation of alpha-synuclein is connected to the pathology of Parkinson's disease and prolyl oligopeptidase (PREP) accelerates the aggregation of alpha-synuclein in vitro. The aim of this study was to investigate the effects of a PREP inhibitor, KYP-2047, on alpha-synuclein aggregation in cell lines overexpressing wild-type or A30P/A53T mutant human alpha-syn and in the brains of two A30P alpha-synuclein 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 (2 x 3 mg.kg(-1) a day). Besides immunohistochemistry and thioflavin S staining, soluble and insoluble alpha-synuclein protein levels were measured by Western blot. alpha-synuclein mRNA levels were quantified by PCR. The colocalization of PREP and alpha-synuclein,and the effect of KYP-2047 on cell viability were also investigated. KEY
RESULTS: In cell lines, oxidative stress induced a robust aggregation of alpha-synuclein,and low concentrations of KYP-2047 significantly reduced the number of cells with alpha-synuclein inclusions while abolishing the colocalization of alpha-synuclein and PREP. KYP-2047 significantly reduced the amount of aggregated alpha-synuclein,and it had beneficial effects on cell viability. In the transgenic mice, a 5-day treatment with the PREP inhibitor reduced the amount of alpha-synuclein immunoreactivity and soluble alpha-synuclein protein in the brain. CONCLUSIONS AND IMPLICATIONS: The results suggest that the PREP may play a role in brain accumulation and aggregation of alpha-synuclein, while KYP-2047 seems to effectively prevent these processes.