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

• DOI: 10.1111/j.1476-5381.2012.01846.x
• Publication Date: 2012-01-10T13:37:40Z
• Authors: TT Myöhänen; MJ Hannula; R Van Elzen; M Gerard; P Van Der Veken; JA García‐Horsman; V Baekelandt; PT Männistö; AM Lambeir
• Keywords: Male; 0301 basic medicine; Serine Proteinase Inhibitors; Proline; Cell Survival; Reverse Transcriptase Polymerase Chain Reaction; Blotting, Western; Serine Endopeptidases; Cell Culture Techniques; Brain; Mice, Transgenic; Motor Activity; Mice, Inbred C57BL; Mice; Oxidative Stress; 03 medical and health sciences; Microscopy, Fluorescence; Parkinsonian Disorders; Cell Line, Tumor; Animals; Humans; Prolyl Oligopeptidases

BACKGROUND AND PURPOSEThe aggregation of α‐synuclein is connected to the pathology of Parkinson's disease and prolyl oligopeptidase (PREP) accelerates the aggregation of α‐synucleinin 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 APPROACHCells 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−1a 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 RESULTSIn 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 IMPLICATIONSThe 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.