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A Prolyl Oligopeptidase Inhibitor, KYP-2047, Reduces α-synuclein Protein Levels and Aggregates in Cellular and Animal Models of Parkinson's Disease

A Prolyl Oligopeptidase Inhibitor, KYP-2047, Reduces α-synuclein Protein Levels and Aggregates in Cellular and Animal Models of Parkinson's Disease

T T Myöhänen, M J Hannula, R Van Elzen, M Gerard, P Van Der Veken, J A García-Horsman, V Baekelandt, P T Männistö, A M Lambeir

Br J Pharmacol. 2012 Jun;166(3):1097-113.

PMID: 22233220

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP796874992	KYP-2047		796874-99-2	Price

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