Involvement of RNA-editing enzyme and multi-factor to motor neuron death in patients with sporadic amyotrophic lateral sclerosis

• Project/Area Number: 21591071
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: University of Tsukuba
• Principal Investigator: TAKUMA Hiroshi 筑波大学, 医学医療系, 講師 (00326258)
• Co-Investigator(Kenkyū-buntansha): TAMAOKA Akira 筑波大学, 医学医療系, 教授 (50192183)
• Co-Investigator(Renkei-kenkyūsha): KWAK Shin 東京大学, 医学部・附属病院, 准教授 (40160981)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 筋萎縮性側索硬 サ症 / RNA編集 / 多因子 / 電気穿孔法 / TDP-43 / 筋萎縮性側索硬化症 / 細胞死 / ADAR2 / ウイルスベクター / Progranulin / 初代培養系

Research Abstract

To examine the effect of multi-factorial involvement, such as RNA-editing enzyme, in the typical neurodegenerative disease, amyotrophic lateral sclerosis (ALS), I established the model for neuronal cell death. For in vitro study, adenovirus system was developed, and for in vivo study the gene-transfer system by electroporation for embryo mice was developed. These systems are very useful for studying multi-factorial system because many genes can be introduced into simultaneously and easily.

Research Products

• [Journal Article] RNA editing活性低下とTDP-43病理 (2012)
  • Author(s): 郭伸
  • Journal Title: 孤発性ALS運動ニューロンにおける疾患特異的両分子異常の分子連関 Volume: (印刷中)
• [Journal Article] The abnormal processing of TDP-43 is not an upstream event of reduced ADAR2 activity in ALS motor neurons (2012)
  • Author(s): Yamashita T, Hideyama T, Teramoto S, Kwak S.
  • Journal Title: Neurosci Res Volume: 73(2) Pages: 153-60
  • Peer Reviewed
• [Journal Article] RNA editing of the Q/R site of GluA2 in different cultured cell lines that constitutively express different levels of RNA editing enzyme ADAR2 (2012)
  • Author(s): Yamashita T, Tadami C, Nishimoto Y, Hideyama T, Kimura D, Suzuki T, Kwak S
  • Journal Title: Neurosci Res Volume: 73(1) Pages: 42-8
  • Peer Reviewed
• [Journal Article] Epitope mapping of antibodies against TDP-43 and detection of protease-resistant fragments of pathological TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration (2012)
  • Author(s): Tsuji H, Nonaka T, Yamashita M, Masuda-Suzukake M, Kametani F, Akiyama H, Mann DM, Tamaoka A, Hasegawa M
  • Journal Title: Biochem Biophys Res Commun Volume: 417(1) Pages: 116-21
  • Peer Reviewed
• [Journal Article] Profound down regulation of the RNA editing enzyme ADAR2 in ALS spinal motorneurons (2012)
  • Author(s): Hideyama T, Yamashita T, Aizawa H, Tsuji S, Kakita A, Takahashi H, Kwak S
  • Journal Title: Neurobiol Dis Volume: 45(3) Pages: 1121-8
  • Peer Reviewed
• [Journal Article] E22Δ Mutation in Amyloid β-Protein Promotes β-Sheet Transformation, Radical Production, and Synaptotoxicity, But Not Neurotoxicity (2011)
  • Author(s): Suzuki T, Murakami K, Izuo N, Kume T, Akaike A, Nagata T, Nishizaki T, Tomiyama T, Takuma H, Mori H, Irie K
  • Journal Title: Int J Alzheimers Dis Pages: 431320-431320
  • Peer Reviewed
• [Journal Article] Molecular Dissection of TDP-43 Proteinopathies (2011)
  • Author(s): Hasegawa M, Nonaka T, Tsuji H, Tamaoka A, Yamashita M, Kametani F, Yoshida M, Arai T, Akiyama H
  • Journal Title: J Mol Neurosci
  • Peer Reviewed
• [Journal Article] When Does ALS Start? ADAR2-GluA2 Hypothesis for the Etiology of Sporadic ALS (2011)
  • Author(s): Hideyama T, Kwak S
  • Journal Title: Front Mol Neurosci Volume: 4 Pages: 33-33
• [Journal Article] 興奮毒性とAMPA受容体編集異常 (2011)
  • Author(s): 日出山拓人, 郭伸
  • Journal Title: Clinical Neuroscience Volume: 29 Pages: 1011-1014
• [Journal Article] A mouse model of amyloid β oligomers : their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo (2010)
  • Author(s): Tomiyama T, Matsuyama S, Iso H, Umeda T, Takuma H, Ohnishi K, Ishibashi K, Teraoka R, Sakama N, Yamashita T, Nishitsuji K, Ito K, Shimada H, Lambert MP, Klein WL, Mori H
  • Journal Title: J Neurosci Volume: 30(14) Pages: 4845-56
  • Peer Reviewed
• [Journal Article] CpG Demethylation Enhances Alpha-Synuclein Expression and Affects the Pathogenesis Parkinson's Disease (2010)
  • Author(s): Matsumoto L, Takuma H, Tamaoka A, Kurisaki H, Date H, Tsuji S, Iwata A
  • Journal Title: PLoSOne Volume: 5(11)
  • NAID: 120007137835
  • Peer Reviewed
• [Journal Article] Oxidative stress up-regulates presenilin 1 in lipid rafts in neuronal cells (2010)
  • Author(s): Oda A, Tamaoka A, Araki W
  • Journal Title: J Neurosci Res Volume: 85(5) Pages: 1137-45
  • Peer Reviewed
• [Journal Article] Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2 (2010)
  • Author(s): Hideyama T, Yamashita T, Suzuki T, Tsuji S, Higuchi M, Seeburg PH, Takahashi R, Misawa H, Kwak S
  • Journal Title: J Neurosci Volume: 30 Pages: 11917-11925
  • Peer Reviewed
• [Journal Article] TDP-43 pathology in sporadic ALS occurs in motor neurons lacking RNA editing enzyme ADAR2 (2010)
  • Author(s): Aizawa H, Sawada J, Hideyama T, Yamashita T, Katayama T, Hasebe N, Kimura T, Yahara O, Kwak S
  • Journal Title: Acta Neuropathol Volume: 120 Pages: 75-84
  • Peer Reviewed
• [Journal Article] Inefficient A-to-I RNA editing and ALS (2010)
  • Author(s): Kwak S
  • Journal Title: 臨床神経学 Volume: 50(11) Pages: 978-978
  • Peer Reviewed
• [Journal Article] Novel etiological and therapeutic strategies for neurodiseases : RNA editing enzyme abnormality in sporadic amyotrophic lateral sclerosis (2010)
  • Author(s): Hideyama T, Yamashita T, Nishimoto Y, Suzuki T, Kwak S
  • Journal Title: J Pharmacol Sci Volume: 113(1) Pages: 9-13
• [Journal Article] TgArc/Arg3.1-d4EGFP indicator mice : a versatile tool to study brain activity changes in vitro and in vivo (2009)
  • Author(s): Grinevich V, Kolleker A, Eliava M, Takada N, Takuma H, Fukazawa Y, Shigemoto R, Kuhl D, Waters J, Seeburg PH, Osten P
  • Journal Title: J Neurosci Methods Volume: 184(1) Pages: 25-36
  • Peer Reviewed
• [Journal Article] Expression of TDP-43 in inflammatory myopathies and other muscle diseases (2009)
  • Author(s): Ishii A, Takuma H, Tsuji H, Ohkoshi N, Tamaoka A
  • Journal Title: Neuromuscular Disorders Volume: 19(8-9) Pages: 651-651
  • Peer Reviewed
• [Journal Article] Effects of antidepressants on GluR2 Q/R site-RNA editing in modified HeLa cell line (2009)
  • Author(s): Sawada J, Yamashita T, Aizawa H, Aburakawa Y, Hasebe N, Kwak S
  • Journal Title: Neurosci Res Volume: 64(3) Pages: 251-8
  • Peer Reviewed
• [Presentation] Pathogenesis of Amyotrophic Lateral Sclerosis and the future therapeutic aspect (2011)
  • Author(s): Takuma H, Tamaoka A
  • Organizer: The first Bonn-Tsukuba Symposium in Medicine
  • Place of Presentation: Tsukuba
  • Year and Date: 2011-12-03
• [Presentation] FTLD-TDPおよびALSに蓄積するTDP-43蛋白の凝集体構造に関する解析 (2011)
  • Author(s): 辻浩史, 野中隆, 新井哲明, 山下万喜子, 亀谷富由樹, 細川雅人, 初田裕幸、高尾昌樹, 村山繁雄, 齊藤祐子, 長谷川成人, 秋山治彦, マン・デービット, 詫間浩, 玉岡晃
  • Organizer: 第30回日本認知症学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2011-11-12
• [Presentation] 変異SOD1を有するALS患者由来iPS細胞の樹立とアストロサイトへの分化 (2011)
  • Author(s): 北岡志保, 月田香代子, 高橋和利, 沖田圭介, 近藤孝之, 吉川勝宇, 山脇聖子, 内藤素子, 鈴木茂彦, 和泉唯信, 梶龍兒, 詫間浩, 玉岡晃, 森田光哉, 中野今治, 川田明広, 中畑龍俊, 高橋良輔, 山中伸弥, 井上治久
  • Organizer: 第34回日本神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2011-09-16
• [Presentation] 変異SOD1を有するALS患者由来iPS細胞の樹立とアストロサイトへの分化 (2011)
  • Author(s): 北岡志保
  • Organizer: 第34回日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2011-09-16
• [Presentation] 封入体筋炎におけるフィラミン染色性の検討 (2011)
  • Author(s): 詫間浩, 石井亜紀子, 石井一弘, 渡邊雅彦, 中馬越清隆, 冨所康志, 塩谷彩子, 玉岡晃
  • Organizer: 第52回日本神経学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-19
• [Presentation] Down regulation of RNA editing enzyme ADAR2 and sporadic ALS (2011)
  • Author(s): Hideyama T, Yamashita T, Aizawa H, Kwak S
  • Organizer: The 22nd International Symposium on MND/ALS
  • Place of Presentation: Sydney
• [Presentation] Abnormal G1uR2 RNA editing and TDP-43 pathology in ALS motor neurons (2011)
  • Author(s): Yamashita T, Hideyama T, Hachiga K, Teramoto S, Kwak S
  • Organizer: 41st Annual Meeting Society for Neuroscience
  • Place of Presentation: Washington DC
• [Presentation] ALS運動ニューロンにおけるRNA編集異常とTDP-43の病理.Abnormal G1uR2 RNA editing and TDP-43 pathology in ALS motorneurons (2011)
  • Author(s): 山下雄也, 日出山拓人, 八賀康介, 寺本さやか, 郭伸
  • Organizer: 第34回神経科学大会
  • Place of Presentation: 横浜
• [Presentation] 神経変性疾患における蛋白癌仮説 (2011)
  • Author(s): 長谷川成人, 野中隆, 辻浩史, 山下万貴子, 増田雅美, 玉岡晃, 村山繁雄, 新井哲明, 秋山治彦
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
• [Presentation] Failure of RNA editing and the pathogenesis of ALS. AAN-JSN Joint Symposium (ALSセッション) (2011)
  • Author(s): 郭伸
  • Organizer: 第52回日本神経学会総会
  • Place of Presentation: 名古屋
• [Presentation] AMPA受容体サブユニットG1uR2のQ/R部位RNA編集率に及ぼす各種薬剤の効果 (2011)
  • Author(s): 澤田潤, 相津仁志, 片山隆行, 長谷部直幸, 山下雄也, 郭伸
  • Organizer: 第52回日本神経学会総会
  • Place of Presentation: 名古屋
• [Presentation] 孤発性ALSにおけるRNA編集異常のメカニズムと運動ニューロン死 (2011)
  • Author(s): 日出山拓人, 山下雄也, 相津仁志, 柿田明美, 高橋均, 辻省次, 鈴木岳史, Seeburg PH, Higuchi M, 高橋良輔, 三津日出巳, 郭伸
  • Organizer: 第52回日本神経学会総会
  • Place of Presentation: 名古屋
• [Presentation] 筋萎縮性側索硬化症患者白血球における新規RNA編集部位の検討 (2010)
  • Author(s): 詫間浩、山下雄也、石井一弘、郭伸、玉岡晃
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京国際フォーラム(東京都)
  • Year and Date: 2010-05-22
• [Presentation] C1ose association of TDP-43 pathology with loss of RNA editing enzyme ADAR2 in motor neurons of sporadic ALS (2010)
  • Author(s): Aizawa H, Sawada J, Hideyama T, Yamashita T, Kwak S
  • Organizer: The 21st International Symposium on MND/ALS
  • Place of Presentation: Orland
• [Presentation] Inefficient G1uA2 RNA editing as a cause or slow death of motor neurons Current understandings and future directions for ALS・First BRI International Symposium 2010 (2010)
  • Author(s): 郭伸
  • Organizer: 新潟大学脳研究所シンポジウム
  • Place of Presentation: 新潟
• [Presentation] Absence of G1uR2RNA editing induces slow death of motor neurons in conditional ADAR2 knockout mice (2010)
  • Author(s): Hideyama T, Yamashita T, Suzuki T, Tsuji S, Higuchi M, Seeburg PH, Tsuji S, Higuchi M, Seeburg PH, Takahashi R, Misawa H, Kwak S
  • Organizer: 40th Annual Meeting Society for Neuroscience
  • Place of Presentation: San Diego
• [Presentation] 孤発性筋萎縮性側索硬化症におけるRNA編集酵素異常.ミニシンポジウム「若手研究者が展開する筋萎縮性側索硬化症研究の将来展望」 (2010)
  • Author(s): 日出山拓人, 山下雄也, 鈴木岳之, Higuchi Miyoko, Peter H Seeburg, 高橋良輔, 辻省次, 三樺日出巳, 郭伸
  • Organizer: 第33回日本神経科学大会
  • Place of Presentation: 神戸
• [Presentation] G1uR2RNA編集異常とTDP-43蛋白のプロセシング異常の分子連関、Analysis for the molecular link between abnormal G1uR2 RNA editing and TDP-43 protein processing (2010)
  • Author(s): 山下雄也, 日出山拓人, 寺本さやか、郭伸
  • Organizer: 第33回神経科学大会
  • Place of Presentation: 神戸
• [Presentation] TDP-43 pathology in sporadic ALS occurs in neurons lacking the RNA editing enzyme ADAR2 (2010)
  • Author(s): Aizawa H, Sawada J, Hideyama T, Yamashita T, Kwak S
  • Organizer: XIIth International Congress on Neuromuscular Disease
  • Place of Presentation: Naples
• [Presentation] 筋萎縮性側索硬化症患者白血球における新規RNA editing部位の検討 (2010)
  • Author(s): 詫間浩, 山下雄也, 石井一弘, 郭伸, 玉岡晃
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京
• [Presentation] 筋萎縮性側索硬化症に蓄積するTDP-43蛋白C末端断片に関する検討 (2010)
  • Author(s): 辻浩史, 長谷川成人, 野中隆, 新井哲明, 山下万貴子, 亀谷富由樹, 秋山治彦, 詫間浩, 冨所康志, 中馬越清隆, 石井亜紀子, 石井一弘, 渡邊雅彦, 玉岡晃
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京
• [Presentation] ヒト剖検脳におけるα-シヌクレイン遺伝子発現とDNAメチル化の解析 (2010)
  • Author(s): 松本ルミネ, 岩田淳, 古和久朋, 詫間浩, 玉岡晃, 栗崎博司, 辻省次
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京
• [Presentation] SOD1遺伝子変異L144FVXを有する家族性ALSの臨床的特徴について (2010)
  • Author(s): 玉岡晃, 辻浩史, 詫間浩, 新井誠, 小幡菜々子, 糸川昌成, 新井哲明, 長谷川成人, 塩谷彩子, 石井亜紀子, 石井一弘, 秋山治彦
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京
• [Presentation] 「Inefficient A-to-I RNA editing and ALS/ALSにおけるRNA editing異常の病因的意義」シンポジウム. Neurodegenerative diseases and RNA/神経疾患とRNA (2010)
  • Author(s): 郭伸
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京
• [Presentation] AMPA受容体サブユニットG1uR2のQ/R部位RNA編集率に及ぼす各種薬剤の効果 (2010)
  • Author(s): 澤田潤, 相澤仁志, 長谷部直幸, 山下雄也, 郭伸
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京
• [Presentation] 孤発性筋萎縮性側索硬化症とRNA編集異常 (2010)
  • Author(s): 日出山拓人, 山下雄也, 相樺仁志, 柿田明美, 高橋均, 辻省次, 郭伸
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京
• [Presentation] Role of RNA editing of G1uR21nRNA in mouse model of sporadic ALS (2009)
  • Author(s): Hideyama T, Yamashita T, Tsuji S, Takahashi R, Misawa H, Suzuki T, Kwak S
  • Organizer: The 20^<th>International Symposium on MND/ALS
  • Place of Presentation: Berlin
• [Presentation] 「ALS治療標的としての興奮性細胞死.Excitotoxicity, old but new vistas to ALS therapy」シンポジウム「神経変性疾患の分子標的治療への新たな展開, Molecular targeted therapy for neurodegenerative disease-new progress」 (2009)
  • Author(s): 郭伸
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋
• [Presentation] 「発症機構から導き出された神経疾患の薬物治療への新たな可能性」.シンポジウム「生体機能と創薬シンポジウム」 (2009)
  • Author(s): 郭伸
  • Organizer: 日本薬学会
  • Place of Presentation: 東京
• [Presentation] ALSにおけるRNA editing.シンポジウム「精神・神経・筋疾患のトランスレーシヨナルリサーチ (2009)
  • Author(s): 郭伸
  • Organizer: 第52回日本神経化学会
  • Place of Presentation: 伊香保
• [Presentation] 「興奮性神経細胞死から見たALS」ALSシンポジウム (2009)
  • Author(s): 郭伸
  • Organizer: 第50回日本神経病理学会
  • Place of Presentation: 高松
• [Presentation] マイクロアレイを用いたRNA編集酵素(ADAR2)の新規基質の同定 (2009)
  • Author(s): 詫間浩, 山下雄也, 郭伸, 玉岡晃
  • Organizer: 第50回日本神経学会総会
  • Place of Presentation: 仙台
• [Presentation] 筋萎縮性側索硬化症(ALS)におけるTDP-43遺伝子とタンパク質に関する検討 (2009)
  • Author(s): 辻浩史, 長谷川成人, 亀谷富由樹, 野 ・イ, 新井哲明, 秋山治彦, 詫間浩, 冨所康志, 中馬越清隆, 石井亜紀子, 石井一弘, 渡邊雅彦, 玉岡晃
  • Organizer: 第50回日本神経学会総会
  • Place of Presentation: 仙台
• [Presentation] AMPA受容体サブユニットG1uR2のQ/R部位RNA編集率に及ぼす各種薬剤の効果 (2009)
  • Author(s): 澤田潤、相津仁志、長谷部直幸、木村隆, 箭原修, 山下雄也、郭伸
  • Organizer: 第50回日本神経学会総会
  • Place of Presentation: 仙台
• [Book] 神経疾患最新の治療 (2012)
  • Author(s): 日出山拓人, 郭伸
  • Publisher: 南江堂(印刷中)
• [Book] Objective evaluation of the severity of parkinsonism using power-law temporal autocorrelation of activity. (2011)
  • Author(s): Pan, W., Yamamoto, Y., Kwak, S
  • Publisher: In Diagnosticsand Rehabilitation of Parkinson's Disease, (Ed Dushanova, J.)
• [Book] アルツハイマー病・認知症.病気と薬パーフェクトBOOK2010 (2010)
  • Author(s): 玉岡晃
  • Publisher: 南山堂(東京)
• [Book] Alzheimer病に対する非薬物療法は.EBM神経疾患の治療2009-2010 (2009)
  • Author(s): 玉岡晃
  • Publisher: 中外医学社
• [Book] In Adolescent Schizophrenia (Ed. by James T. Nillinghouse, Robert P. Trotman) Nova Biomedical Books (2009)
  • Author(s): R Koide, A Tamaoka
  • Publisher: Body image deviationin chronic schizophrenia. new research
• [Book] アルツハイマー病・認知症.病気と薬パーフェクトBOOK 2009 (2009)
  • Author(s): 玉岡晃
  • Publisher: 南山堂, 東京
• [Book] 筋萎縮性側索硬化症(ALS)の基礎研究
  • Author(s): 日出山拓人, 郭伸
  • Publisher: (印刷中)
• [Patent(Industrial Property Rights)] 筋萎縮性側索硬化症の予防及び治療のための医薬 (2009)
  • Inventor(s): 郭伸, 山下雄也, 日出山拓人
  • Industrial Property Rights Holder: 郭伸, 山下雄也, 日出山拓人
  • Filing Date: 2009-07-28