BACKGROUND AND PURPOSE The aggregation of α‐synuclein is connected to the pathology of Parkinson's disease and prolyl oligopeptidase (PREP) accelerates the aggregation of α‐synuclein in vitro. The aim of this study was to investigate the effects of a PREP inhibitor, KYP‐2047, on α‐synuclein aggregation in cell lines overexpressing wild‐type or A30P/A53T mutant human α‐syn and in the brains of two A30P α‐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 × 3 mg·kg−1 a day). Besides immunohistochemistry and thioflavin S staining, soluble and insoluble α‐synuclein protein levels were measured by Western blot. α‐synuclein mRNA levels were quantified by PCR. The colocalization of PREP and α‐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 α‐synuclein,and low concentrations of KYP‐2047 significantly reduced the number of cells with α‐synuclein inclusions while abolishing the colocalization of α‐synuclein and PREP. KYP‐2047 significantly reduced the amount of aggregated α‐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 α‐synuclein immunoreactivity and soluble α‐synuclein protein in the brain. CONCLUSIONS AND IMPLICATIONS The results suggest that the PREP may play a role in brain accumulation and aggregation of α‐synuclein, while KYP‐2047 seems to effectively prevent these processes.

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Prolyl oligopeptidase (POP) is a serine protease that hydrolyzes peptides shorter than 30-mer. Some evidence has recently been obtained that POP can generate protein-protein interactions and therefore participate in various physiological and pathological events. Several studies have reported that POP may be involved in neurogenesis since its activity increases during development and can be found in the nucleus of proliferating tissues. In cell cultures, POP has been shown to be localized in the nucleus, but only early in the development, since during maturation it is moved to the cytosol. We have now studied for the first time the expression of POP protein, its enzymatic activity and nuclear localization in vivo in the developing rat brain. We observed that enzymatic activity of POP is highest on embryonic day 18 while the protein amounts reach their peak at birth. Furthermore, POP is located in the nucleus only early in the development but is transferred to the cytosol already before parturition. Our in vivo results confirm the previous cell culture results supporting the role of POP in neurogenesis. A discordance of antenatal protein amounts and enzymatic activities is suggesting a tight regulation of POP activity and possibly even a nonhydrolytic role at that stage.

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