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

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

SUBMITTER: Myohanen TT

PROVIDER: S-EPMC3417432 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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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.

Myöhänen T T TT Hannula M J MJ Van Elzen R R Gerard M M Van Der Veken P P García-Horsman J A JA Baekelandt V V Männistö P T PT Lambeir A M AM

British journal of pharmacology 20120601 3

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>Cells were exposed t ...[more]

PMID: 22233220

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Project description:Decreased clearance of α-synuclein (aSyn) and aSyn protein misfolding and aggregation are seen as major factors in the pathogenesis of Parkinson's disease (PD) and other synucleinopathies that leads to disruption in neuronal function and eventually to cell death. Prolyl oligopeptidase (PREP) can accelerate the aSyn aggregation process, while inhibition of PREP by a small molecule inhibitor decreases aSyn oligomer formation and enhances its clearance via autophagy in different aSyn overexpressing cell types and in transgenic PD animal models. In this study, we investigated the impact of chronic PREP inhibition by a small molecule inhibitor, 4-phenylbutanoyl-l-prolyl-2(S)-cyanopyrrolidine (KYP-2047), on aSyn oligomerization, clearance, and underlying spontaneous motor behavior in a virus vector-based aSyn overexpression mouse model 4 weeks after aSyn microinjections and after the onset of symptomatic forepaw bias. Following 4 weeks of PREP inhibition, we saw an improved spontaneous forelimb use in mice that correlated with a decreased immunoreactivity against oligomer-specific forms of aSyn. Additionally, KYP-2047 had a trend to enhance dopaminergic systems activity. Our results suggest that PREP inhibition exhibits a beneficial effect on the aSyn clearance and aggregation in a virus mediated aSyn overexpression PD mouse model and that PREP inhibitors could be a novel therapeutic strategy for synucleinopathies.Significance statementAlpha-synuclein (aSyn) has been implicated in Parkinson's disease, with aSyn aggregates believed to exert toxic effects on neurons, while prolyl oligopeptidase (PREP) has been shown to interact with aSyn both in cells and cell free conditions, thus enhancing its aggregation. We demonstrate the possibility to abolish motor imbalance caused by aSyn viral vector injection with chronic 4 week PREP inhibition by a potent small-molecule PREP inhibitor, 4-phenylbutanoyl-l-prolyl-2(S)-cyanopyrrolidine (KYP-2047). Treatment was initiated postsymptomatically, 4 weeks after aSyn injection. KYP-2047-treated animals had a significantly decreased amount of oligomeric aSyn particles and improved dopamine system activity compared to control animals. To our knowledge, this is the first time viral overexpression of aSyn has been countered and movement impairments abolished after their onset.

Project description:Parkinson's disease is a common neurodegenerative disorder marked by the accumulation of the protein alpha synuclein. Studies have indicated the role of prolyl oligopeptidase (POP), a serine protease, in alpha synuclein accumulation. Therefore, POP emerges as an attractive medicinal target. Traditionally, most of the early medicines have been plant-based owing to their ready availability and negligible side effects. Alkaloids owing to their neurotransmitter modulatory, anti-amyloid, anti-oxidant, and anti-inflammatory activities have shown potential in neurodegenerative disease. In this work, we computationally evaluated alkaloid class of phytochemicals for their therapeutic efficacy against POP. Alkaloids were retrieved from the publically available database, Chemical Entities of Biological Interest (ChEBI), and screened for their drug likeness (Lipinski's rule of 5) and absorption, distribution, metabolism, and excretion, and toxicity (ADMET) in Discovery Studio by ensuring parameters suitable for a central nervous system disease such as blood-brain barrier (BBB) level set to ≤2, absorption level set to 0 and solubility level permitted set to 2, 3, or 4. Next, molecular docking was performed to learn about the affinity of the filtered alkaloids with the POP. Subsequently, molecular dynamic simulations were conducted to assess the reliability and stability of the alkaloid-protein complex. Our study identified metergoline, pipercallosine, celacinnine, lobeline, cystodytin G, lycoperine A, hookerianamide J, and martefragin A as putative lead compounds against POP. Among these, metergoline, pipercallosine, hookerianamide J, and lobeline showed the most promising results. These compounds demonstrated better or equivalent molecular docking scores in comparison to three POP inhibitors that had reached clinical trials, i.e., Z-321, S-17092, and JTP-4819. MD simulations indicated that these compounds remained intact at the active site while adhering to the binding mode and interaction patterns as that of the reported inhibitors. The research conducted here, therefore, provides evidence for conducting in vitro POP inhibitory studies of these newly identified plant-based POP inhibitors.

Dataset Information

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

Publications

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

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