A prolyl oligopeptidase inhibitor, KYP-2047, reduces alpha-synuclein protein levels and aggregates in cellular and animal models of Parkinson's disease

: Myohanen TT, Hannula MJ, Van Elzen R, Gerard M, Van der Veken P, Garcia-Horsman JA, Baekelandt V, Mannisto PT, Lambeir AM

Publisher: WILEY-BLACKWELL

: 2012

British Journal of Pharmacology

: BRITISH JOURNAL OF PHARMACOLOGY

: BRIT J PHARMACOL

: 166

: 3

: 1097

: 1113

: 17

: 0007-1188

DOI: https://doi.org/10.1111/j.1476-5381.2012.01846.x

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