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パーキンソン病とその類縁疾患 2
Parkinson's Disease and Related Disorders 2

開催日 2014/9/12
時間 18:10 - 19:10
会場 Room I(311+312)
Chairperson(s) 野元 正弘 / Masahiro Nomoto (愛媛大学大学院医学系研究科 薬物療法・神経内科学 / Department of Neurology and Clinical Pharmacologu, Ehime University, Graduate School of Medecine, Japan)
村田 美穂 / Miho Murata (国立精神・神経医療センター 病院・神経内科 / Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Japan)

Genetic co-regulation of the nigrostriatal dopaminergic function by V-1 gene via the Rho-MAL-SRF pathway in vitro and in vivo

  • O2-I-6-1
  • 川畑 伊知郎 / Ichiro Kawahata:1 延新 来 / Lai Yanxin :1 大宅 史織 / Shiori Ohtaku:1 森田 淳一 / Junichi Morita:1 加藤 茂樹 / Shigeki Kato:2 富岡 佳久 / Yoshihisa Tomioka:3 田渕 明子 / Akiko Tabuchi:3 福地 守 / Mamoru Fukuchi:3 津田 正明 / Masaaki Tsuda:4 一瀬-鷲見 千穂 / Chiho Sumi-Ichinose:4 近藤 一直 / Kazunao Kondo:4 泉 安彦 / Yasuhiko Izumi:5 久米 利明 / Yoshiaki Kume:5 赤池 昭紀 / Akinori Akaike:5 大橋 一正 / Kazumasa Ohashi:6 水野 健作 / Kensaku Mizuno:6 一瀬 宏 / Hiroshi Ichinose:7 小林 和人 / Kazuto Kobayashi:2 山国 徹 / Tohru Yamakuni:1 
  • 1:東北大院薬 / Graduate School of Pharmaceutical Sciences, Tohoku University, Japan 2:福島県立医大医 / Inst of Biomedical Sci, Fukushima Med Univ, Fukushima, Japan 3:富山大院薬 / Grad Sch of Med and Pharm Sci, Univ of Toyama, Japan 4:藤田保健衛生大医 / Sch of Med, Fujita Health Univ, Japan 5:京都大院薬 / Grad Sch of Pharm Sciences, Kyoto Univ, Japan 6:東北大院理 / Grad Sch of Life Sci, Tohoku Univ, Japan 7:東工大院生命理工 / Grad Sch of Biosci and Biotech, Tokyo Inst of Tech, Japan 

Tyrosine hydroxylase (TH) and dopa decarboxylase (DDC) are essential enzymes for dopamine (DA) biosynthesis. We found previously that V-1 overexpression elevates TH and DDC mRNA levels in culture (JBC 1998), raising the possibility of application of V-1 gene therapy for Parkinson's disease (PD). Here, we provide the first evidence for a novel regulatory mechanism of coordinated gene expression of TH/DDC/Nurr1 by V-1, an actin dynamics regulator. Knockdown of endogenous V-1 reduced TH, DDC and Nurr1 expression with reduction of SRF-mediated transcription in cultured mesencephalic neurons (DA neurons), which concomitantly decreased RhoA activity and actin assembly. Conversely, V-1 overexpression promoted RhoA activity and actin assembly to elevate TH/DDC/Nurr1 gene expression, accompanied with enhancement of MAL nuclear import and DA biosynthesis. ChIP-PCR assay with anti-SRF antibody identified the V-1 regulated SRF-binding in the promoter region of above three genes. Interestingly, VSV-G/V-1 transfection alleviated MPTP-induced neurodegeneration of DA neurons and recovered impaired expression levels of TH, DDC, Nurr1 and VMAT2 as well as decreased cofilin phosphorylation and SRF-mediated transcription. Injection of VSV-G/V-1 into the SNc of C57BL6 mice also elevated TH, DDC, Nurr1 and VMAT2 levels in nigrostriatum in vivo and augmented DA biosynthesis without an increase of L-DOPA, which caused no abnormal behavior. We conclude that V-1 facilitates RhoA-actin signaling, thereby inducing MAL nuclear accumulation, which activates the transcription of SRF target genes, including TH/DDC/Nurr1 gene in dopaminergic system, indicating V-1's potential benefit for safe and fundamental therapy of PD.

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