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.
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 transgenicmouse 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.
Authors: Jarkko I Venäläinen; J Arturo Garcia-Horsman; Markus M Forsberg; Aaro Jalkanen; Erik A A Wallén; Elina M Jarho; Johannes A M Christiaans; Jukka Gynther; Pekka T Männistö Journal: Biochem Pharmacol Date: 2006-01-06 Impact factor: 5.858
Authors: Antony A Cooper; Aaron D Gitler; Anil Cashikar; Cole M Haynes; Kathryn J Hill; Bhupinder Bhullar; Kangning Liu; Kexiang Xu; Katherine E Strathearn; Fang Liu; Songsong Cao; Kim A Caldwell; Guy A Caldwell; Gerald Marsischky; Richard D Kolodner; Joshua Labaer; Jean-Christophe Rochet; Nancy M Bonini; Susan Lindquist Journal: Science Date: 2006-06-22 Impact factor: 47.728
Authors: S Yu; X Li; G Liu; J Han; C Zhang; Y Li; S Xu; C Liu; Y Gao; H Yang; K Uéda; P Chan Journal: Neuroscience Date: 2007-02-01 Impact factor: 3.590
Authors: Y Shishido; M Furushiro; S Tanabe; A Taniguchi; S Hashimoto; T Yokokura; S Shibata; T Yamamoto; S Watanabe Journal: Pharm Res Date: 1998-12 Impact factor: 4.200
Authors: Aaro J Jalkanen; Katja A Puttonen; Jarkko I Venäläinen; Veijo Sinervä; Anne Mannila; Sirja Ruotsalainen; Elina M Jarho; Erik A A Wallén; Pekka T Männistö Journal: Basic Clin Pharmacol Toxicol Date: 2007-02 Impact factor: 4.080
Authors: Leonid Yavich; Mari Oksman; Heikki Tanila; Petri Kerokoski; Mikko Hiltunen; Thomas van Groen; Jukka Puoliväli; Pekka T Männistö; Arturo García-Horsman; Ewen MacDonald; Konrad Beyreuther; Tobias Hartmann; Pekka Jäkälä Journal: Neurobiol Dis Date: 2005-11 Impact factor: 5.996
Authors: Timo T Myöhänen; Jarkko I Venäläinen; Erkki Tupala; J Arturo Garcia-Horsman; Riitta Miettinen; Pekka T Männistö Journal: Neurochem Res Date: 2007-03-31 Impact factor: 3.996
Authors: Päivi Lindholm; Merja H Voutilainen; Juha Laurén; Johan Peränen; Veli-Matti Leppänen; Jaan-Olle Andressoo; Maria Lindahl; Sanna Janhunen; Nisse Kalkkinen; Tõnis Timmusk; Raimo K Tuominen; Mart Saarma Journal: Nature Date: 2007-07-05 Impact factor: 49.962
Authors: Tommi P Kilpeläinen; Jonna K Tyni; Maija K Lahtela-Kakkonen; Tony S Eteläinen; Timo T Myöhänen; Erik A A Wallén Journal: ACS Med Chem Lett Date: 2019-11-11 Impact factor: 4.345
Authors: Ulrika H Julku; Anne E Panhelainen; Saija E Tiilikainen; Reinis Svarcbahs; Anne E Tammimäki; T Petteri Piepponen; Mari H Savolainen; Timo T Myöhänen Journal: Mol Neurobiol Date: 2016-12-13 Impact factor: 5.590
Authors: Mari H Savolainen; Christopher T Richie; Brandon K Harvey; Pekka T Männistö; Kathleen A Maguire-Zeiss; Timo T Myöhänen Journal: Neurobiol Dis Date: 2014-04-16 Impact factor: 5.996