Prolyl Oligopeptidase Regulates Dopamine Transporter Phosphorylation in the Nigrostriatal Pathway of Mouse
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Alpha-synuclein is the main component of Lewy bodies, a histopathological finding of Parkinson’s disease. Prolyl oligopeptidase (PREP) is a serine protease that binds to α-synuclein and accelerates its aggregation in vitro. PREP enzyme inhibitors have been shown to block the α-synuclein aggregation process in vitro and in cellular models, and also to enhance the clearance of α-synuclein aggregates in transgenic mouse models. Moreover, PREP inhibitors have induced alterations in dopamine and metabolite levels, and dopamine transporter immunoreactivity in the nigrostriatal tissue. In this study, we characterized the role of PREP in the nigrostriatal dopaminergic and GABAergic systems of wild-type C57Bl/6 and PREP knockout mice, and the effects of PREP overexpression on these systems. Extracellular concentrations of dopamine and protein levels of phosphorylated dopamine transporter were increased and dopamine reuptake was decreased in the striatum of PREP knockout mice, suggesting increased internalization of dopamine transporter from the presynaptic membrane. Furthermore, PREP overexpression increased the level of dopamine transporters in the nigrostriatal tissue but decreased phosphorylated dopamine transporters in the striatum in wild-type mice. Our results suggest that PREP regulates the function of dopamine transporter, possibly by controlling the phosphorylation and transport of dopamine transporter into the striatum or synaptic membrane.
KeywordsProlyl oligopeptidase PREP Dopamine Dopamine transporter DAT Microdialysis
This work was supported by grants from the Academy of Finland (267788 and 2737991), University of Helsinki research grants, Jane and Aatos Erkko Foundation and from the Sigrid Juselius Foundation to TTM. Authors would like to thank Liisa Lappalainen and Susanna Norrbacka for excellent technical assistance.
Compliance with Ethical Standards
Conflict of Interest
The authors declare no competing financial interests.
This work was supported by grants from the Academy of Finland (267788 and 2737991), University of Helsinki research grants, Jane and Aatos Erkko Foundation and from the Sigrid Juselius Foundation to TT Myöhänen.
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