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Dopamine release via the vacuolar ATPase V0 sector c-subunit,confirmed in N18 neuroblastoma cells,results in behavioral recovery in hemiparkinsonian mice
Authors:Duo Jin  Shin-ichi Muramatsu  Nobuaki Shimizu  Shigeru Yokoyama  Hirokazu Hirai  Kiyofumi Yamada  Hong-Xiang Liu  Chiharu Higashida  Minako Hashii  Akihiko Higashida  Masahide Asano  Shoji Ohkuma  Haruhiro Higashida
Affiliation:1. Kanazawa University, 21st Century Center of Excellence Program on Innovative Brain Science on Development, Learning and Memory, Kanazawa 920-8640, Japan;2. Department of Biophysical Genetics, Kanazawa University Graduate School of Medicine, Kanazawa 920-8640, Japan;3. Division of Neurology, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan;4. Institute of Nature and Environmental Technology, Kanazawa University, Kanazawa 920-1192, Japan;5. Department of Neurophysiology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan;6. Laboratory of Neuropsychopharmacology, School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192, Japan;g Department of Biochemistry, School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192, Japan;h Advanced Science Research Center, Kanazawa University, Kanazawa 920-8640, Japan;i Ministry of Education, Culture, Sports, Science and Technology, Strategic Research Program for Brain Science, Tokyo 100-8959, Japan
Abstract:A 16-kDa proteolipid, mediatophore, in Torpedo electric organs mediates Ca2+-dependent acetylcholine release. Mediatophore is identical to the pore-forming stalk c-subunit of the V0 sector of vacuolar proton ATPase (ATP6V0C). The function of ATP6V0C in the mammalian central nervous system is not clear. Here, we report transfection of adeno-associated viral vectors harboring rat ATP6V0C into the mouse substantia nigra, in which high potassium stimulation increased overflow of endogenous dopamine (DA) measured in the striatum by in vivo microdialysis. Next, in the striatum of 6-hydroxydopamine-lesioned mice, a model of Parkinson’s disease (PD), human tyrosine hydroxylase, aromatic l-amino-acid decarboxylase and guanosine triphosphate cyclohydrolase 1, together with or without ATP6V0C, were expressed in the caudoputamen for rescue. Motor performance on the accelerating rotarod test and amphetamine-induced ipsilateral rotation were improved in the rescued mice coexpressing ATP6V0C. [3H]DA, taken up into cultured N18 neuronal tumor cells transformed to express ATP6V0C, was released by potassium stimulation. These results indicated that ATP6V0C mediates DA release from nerve terminals in the striatum of DA neurons of normal mice and from gene-transferred striatal cells of parkinsonian mice. The results suggested that ATP6V0C may be useful as a rescue molecule in addition to DA-synthetic enzymes in the gene therapy of PD.
Keywords:Mediatophore   ATPase   Dopamine   Parkinson disease   Gene therapy
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