1. A prolyl oligopeptidase inhibitor, KYP-2047, reduces alpha-synuclein protein levels and aggregates in cellular and animal models of Parkinson's disease
- Author
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R Van Elzen, Melanie Gérard, J.A. Garcia-Horsman, Anne-Marie Lambeir, M.J. Hannula, Timo T. Myöhänen, Pekka T. Männistö, Veerle Baekelandt, and P. Van der Veken
- Subjects
Male ,animal diseases ,Cell Culture Techniques ,Oligopeptidase ,Protein aggregation ,medicine.disease_cause ,Mice ,0302 clinical medicine ,heterocyclic compounds ,0303 health sciences ,medicine.diagnostic_test ,Reverse Transcriptase Polymerase Chain Reaction ,Pharmacology. Therapy ,Serine Endopeptidases ,Brain ,Research Papers ,3. Good health ,Blot ,alpha-Synuclein ,Prolyl Oligopeptidases ,Genetically modified mouse ,Serine Proteinase Inhibitors ,Proline ,Cell Survival ,Blotting, Western ,Mice, Transgenic ,Motor Activity ,Biology ,Transfection ,03 medical and health sciences ,Parkinsonian Disorders ,Western blot ,Cell Line, Tumor ,mental disorders ,medicine ,Animals ,Humans ,Viability assay ,030304 developmental biology ,Pharmacology ,Colocalization ,Molecular biology ,nervous system diseases ,Mice, Inbred C57BL ,Oxidative Stress ,Microscopy, Fluorescence ,nervous system ,health occupations ,030217 neurology & neurosurgery ,Oxidative stress - 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.
- Published
- 2012
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