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Study on the cellular distribution and molecular function of ALS2, a product of the novel causative gene for famrlial ALS

Research Project

Project/Area Number 14380361
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurochemistry/Neuropharmacology
Research InstitutionTokai University

Principal Investigator

HADANO Shinji  Tokai University, Medical Research Institute, Associate Professor, 総合医学研究所, 助教授 (60281375)

Co-Investigator(Kenkyū-buntansha) OSUGA Hitoshi  Tokai University, Medical Research Institute, Associate Professor, 総合医学研究所, 非常勤助教授 (60203775)
TANAKA Kazunori  Tokai University, School of Medicine, Assistant Researcher, 医学部, 助手 (10338767)
Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥14,800,000 (Direct Cost: ¥14,800,000)
Fiscal Year 2004: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 2003: ¥4,700,000 (Direct Cost: ¥4,700,000)
Fiscal Year 2002: ¥5,800,000 (Direct Cost: ¥5,800,000)
Keywordsamyotrophic laterel sclerosis / familial ALS / ALS2 gene / motor neuron / neurodegenerative disease / guanine nucleotide exchange factor / small GTPase / vesicle trafficking / 細胞内膜・小胞移送 / タンパク質ドメイン
Research Abstract

The aim of this study was to delineate molecular function of ALS2, a causative gene product underlying a number of recessive motor neuron diseases, thereby clarifying the molecular mechanisms for neuronal cell dysfunction and death resulted from loss of function mutations in the ALS2 gene. We have carried out the following four sets of molecular, biochemical, and cell biological studies; 1) immunocytochemical analysis of the subcellular localization of ALS2, 2) identification of the target small GTPases for ALS2, 3) identification of the ALS2 associating/binding factors, and 4) exploration of the biochemical signal pathways mediated by ALS2. We here demonstrate that ALS2 specifically binds to small GTPase Rab5 and functions as a GEF for Rab5. Ectopically expressed ALS2 localizes with Rab5 onto early endosomal compartments, and stimulates the enlargement of endosomes in the cultured neuronal and non-neuronal cells. The carboxy-terminus of ALS2 carrying the MORN/VPS9 domain mediates not only the activation of Rab5 via a guanine-nucleotide exchanging reaction, but also the endosomal localization for ALS2, thereby leading to endosome fusions by activating the Rab5-EEAI-SNARE molecular pathway. We have also shown that ALS2 forms a homophilic oligomer through its distinct C-terminal regions. This homo-oligomerization is crucial for the Rab5GEF activity and the ALS2-mediated endosome enlargement in the cells. Lastly, we have identified a novel ALS2 homologous gene, ALS2 C-terminal like (ALS2CL), which is a novel factor modulating the Rab5-mediated endosome dynamics in the cells. Taken together, a perturbation of the endosomal dynamics, which is resulted from a loss of ALS2 Rab5-GEF activity, might be a key molecular basis underlying neuronal dysfunction and degeneration in a number of motor neuron diseases caused by the ALS2 mutations.

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (45 results)

All 2005 2004 2003 2002 Other

All Journal Article (31 results) Book (2 results) Publications (12 results)

  • [Journal Article] A Dopamine D4 receptor antagonist attenuates ischemia-induced neuronal cell damage viaupregulation of neuronal apoptosis inhibitory protein.2005

    • Author(s)
      Yoshinori Okada
    • Journal Title

      J.Cereb.Blood Flow Metab. (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A Dopamine D4 receptor antagonist attenuates ischemia-induced neuronal cell damage via upregulation of neuronal apoptosis inhibitory protein.2005

    • Author(s)
      Okada, Y., Sakai, H., Kohiki, E., Suga, E., Yanagisawa, Y., Tanaka, K., Hadano, S., Osuga, H., Ikeda, J.-E.
    • Journal Title

      J.Cereb.Blood Flow Metab. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Genes for amyotrophic lateral sclerosis.2005

    • Author(s)
      Hadano, S.
    • Journal Title

      Yobou Igaku Jiten (Asakura Publisher) (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Novel nuclear shuttle proteins, HDBP1 and HDBP2, bind to neuronal cell specificcis-regulatory element in the promoter for the human Huntington's disease2004

    • Author(s)
      Kazunori Tanaka
    • Journal Title

      J.Biol.Chem. 279

      Pages: 7275-7286

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Homo-oligomerization of ALS2 through its unique carboxy-terminal region is essential for the ALS2-associated Rab5 guanine nucleotide exchange activity and its regulatory function on endosome trafficking.2004

    • Author(s)
      Ryota Kunita
    • Journal Title

      J.Biol.Chem. 279

      Pages: 38626-38635

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ALS2CL, the novel protein highly homologous to the carboxy-terminal half of ALS2, binds to Rab5 and modulates endosome dynamics.2004

    • Author(s)
      Shinji Hadano
    • Journal Title

      FEBS Lett. 575

      Pages: 64-70

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Novel nuclear shuttle proteins, HDBP1 and HDBP2, bind to neuronal cell specific cis-regulatory element in the promoter for the human Huntington's disease gene.2004

    • Author(s)
      Tanaka, K., Shouguchi-Miyata, J., Miyamoto, N., Ikeda, J.-E.
    • Journal Title

      J.Biol.Chem. 279 (8)

      Pages: 7275-7286

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] (2004) Homo-oligomerization of ALS2 through its unique carboxy-terminal region is essential for the ALS2-associated Rab5 guanine nucleotide exchange activity and its regulatory function on endosome trafficking.2004

    • Author(s)
      Kunita, R., Otomo, A., Mizumura, H., Suzuki, K., Showguchi-Miyata, J., Yanagisawa, Y., Hadano, S., Ikeda, J.-E.
    • Journal Title

      J.Biol.Chem. 279 (37)

      Pages: 38626-38635

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ALS2CL, the novel protein highly homologous to the carboxy-terminal half of ALS2, binds to Rab5 and modulates endosome dynamics.2004

    • Author(s)
      Hadano, S., Otomo, A., Suzuki-Utsunomiya, K., Kunita, R., Yanagisawa, Y., Showguchi-Miyata, J., Mizumura, H., Ikeda, J.-E.
    • Journal Title

      FEBS Lett. 575 (1-3)

      Pages: 64-70

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Homo-oligomerization of ALS2 through its unique carboxy-terminal region is essential for the ALS2-associated Rab5 guanine nucleotide exchange activity and its regulatory function on endosome trafficking.2004

    • Author(s)
      Ryota Kunita
    • Journal Title

      J.Biol.Chem. 279・37

      Pages: 38626-38635

    • Related Report
      2004 Annual Research Report
  • [Journal Article] ALS2CL, the novel protein highly homologous to the carboxy-terminal half of ALS2, binds to Rab5 and modulates endosome dynamics.2004

    • Author(s)
      Shinji Hadano
    • Journal Title

      FEBS Lett. 575・1-3

      Pages: 64-70

    • Related Report
      2004 Annual Research Report
  • [Journal Article] ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics.2003

    • Author(s)
      Asako Otomo
    • Journal Title

      Hum.Mol.Genet. 12

      Pages: 1671-1687

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Single-nucleotide polymorphisms in uncoding regions of ALS2 gene of Japanese patients with autosomal-recessive amytrophic lateral sclerosis.2003

    • Author(s)
      Isao Nagano
    • Journal Title

      Neurol.Res 25

      Pages: 505-509

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 新しい家族性筋萎縮性側索硬化症遺伝子:ALS2-運動ニューロン疾患における分子接点2003

    • Author(s)
      秦野 伸二
    • Journal Title

      医学のあゆみ 205

      Pages: 119-123

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics.2003

    • Author(s)
      Otomo, A., Hadano, S., Okada, T., Mizumura, H., Kunita, R., Nishijima, H., Showguchi-Miyata, J., Yanagisawa, Y., Kohiki, E., Suga, E., Yasuda, M., Osuga, H., Nishimoto, T., Naurumiya, S., Ikeda, J.-E.
    • Journal Title

      Hum.Mol.Genet. 12 (14)

      Pages: 1671-1687

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Single-nucleotide polymorphisms in uncoding regions of ALS2 gene of Japanese patients with autosomal-recessive amyotrophic lateral sclerosis.2003

    • Author(s)
      Nagano, I., Murakami, T., Shiote, M., Manabe, Y., Hadano, S., Yanagisawa, Y., Ikeda, J.-E., Abe, K.
    • Journal Title

      Neurol.Res. 25 (5)

      Pages: 505-509

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ALS2, the novel gene for a form of recessive amyotrophic lateral sclerosis. -implication in the pathogenesis for motor neuron diseases.2003

    • Author(s)
      Hadano, S.
    • Journal Title

      Igaku no Ayumi 205 (2)

      Pages: 119-123

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Functional human NAIP promoter and transcriptional elements of the human NAIP and ΨNAIP genes.2002

    • Author(s)
      Ming Xu
    • Journal Title

      Biochim.Biophys.Acta 1574

      Pages: 35-50

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Unstable transmission of the RS447 human megasatellite tandem repetitive sequence that contains the USP17 gene encoding a functional deubiquitinating enzyme.2002

    • Author(s)
      Takeya Okada
    • Journal Title

      Hum.Genet. 110

      Pages: 302-313

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis.2002

    • Author(s)
      Roshni R.Singaraja
    • Journal Title

      Hum.Mol.Genet. 11

      Pages: 2815-2828

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 家族性ALSの新たな遺伝子2002

    • Author(s)
      秦野 伸二
    • Journal Title

      BRAIN MEDICAL 14

      Pages: 47-54

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ALSの原因遺伝子2002

    • Author(s)
      秦野 伸二
    • Journal Title

      生化学 74

      Pages: 483-489

    • NAID

      10008692567

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 筋萎縮性側索硬化症原因遺伝子の同定とゲノム研究2002

    • Author(s)
      秦野 伸二
    • Journal Title

      ゲノム医学 2

      Pages: 231-240

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Functional human NAIP promoter and transcriptional elements of the human NAIP and ΨNAIP gene2002

    • Author(s)
      Xu, M., Okada, T., Sakai, H., Miyamoto, N., Yanagisawa, Y., MacKenzie, A.E., Hadano, S., Ikeda, J.-E.
    • Journal Title

      Biochim.Biophys.Acta 1574 (1)

      Pages: 35-50

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Unstable transmission of the RS447 human megasatellite tandem repetitive sequence that contains the USP17 gene encoding a functional deubiquitinating enzyme.2002

    • Author(s)
      Okada, T., Gondo, Y., Goto, J., Kanazawa, I., Hadano, S., Ikeda, J.-E.
    • Journal Title

      Hum.Genet. 110 (4)

      Pages: 302-313

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis.2002

    • Author(s)
      Singaraja, R.R., Hadano, S., Metzler, M., Givan, S., Wellington, C.L, Warby, S., Yanai, A., Gutekunst, C.-A., Leavitt, B.R., Yi, H., Fichter, K., Gan, L, McCutcheon, K., Chopra, V., Michel, J., Hersch, S.M., Ikeda, J.-E., Hayden, M.R.
    • Journal Title

      Hum.Mol.Genet. 11 (23)

      Pages: 2815-2828

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The novel gene for the familial ALS.2002

    • Author(s)
      Hadano, S.
    • Journal Title

      BRAIN MEDICAL 14 (1)

      Pages: 47-54

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Causative genes for familial amyotrophic lateral sclerosis.2002

    • Author(s)
      Hadano, S.
    • Journal Title

      Seikagaku 74 (6)

      Pages: 483-489

    • NAID

      10008692567

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Genetic and genomic approaches for identification of genes underlying amyotrophic lateral sclerosis.2002

    • Author(s)
      Hadano, S.
    • Journal Title

      Genome Med. 2 (3)

      Pages: 231-240

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The causative gene for familial ALS2.2002

    • Author(s)
      Hadano, S., Ikeda, J.-E.
    • Journal Title

      Nou Kinou No Kaimei (Gaia Publisher)

      Pages: 299-305

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A Dopamine D4 receptor antagonist attenuates ischemia-induced neuronal cell damage via upregulation of neuronal apoptosis inhibitory protein.

    • Author(s)
      Yoshinori Okada
    • Journal Title

      J.Cereb.Blood Flow Metab. (in press)

    • Related Report
      2004 Annual Research Report
  • [Book] 予防医学事典(松島網治, 酒井敏行, 石川昌, 稲寺秀邦編)、116.筋萎縮性側索硬化症原因遺伝子2005

    • Author(s)
      秦野 伸二(分担著)
    • Publisher
      朝倉書店、東京(印刷中)
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] 脳機能の解明-生命科学の主潮流-(赤池紀扶, 東英穂, 阿部康二, 久保千春編)、第8章神経変性疾患の遺伝子異常と病態解明、家族性筋萎縮性側策硬化症2型(ALS2)の原因遺伝子2002

    • Author(s)
      秦野 伸二(分担著)
    • Publisher
      ガイア出版会、福岡
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Asako Otomo: "ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics"Hum.Mol.Genet.. 12・14. 1671-1687 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Isao Nagano: "Single-nucleotide polymorphisms in uncoding regions of ALS2 gene of Japanese patients with autosomal-recessive amyotrophic lateral sclerosis"Neurol.Res.. 25・5. 505-509 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kazunori Tanaka: "Novel nuclear shuttle proteins, HDBP1 and HDBP2, bind to neuronal cell specific cis-regulatory element in the promoter for the human Huntington's disease gene"J.Biol.Chem.. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 秦野 伸二: "新しい家族性筋萎縮性側索硬化症遺伝子:ALS2-運動ニューロン疾患における分子接点"医学のあゆみ. 205・2. 119-123 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 秦野 伸二: "予防医学事典(松島綱治、酒井敏行、石川昌、稲寺秀邦編)、116.筋萎縮性側索硬化症原因遺伝子"朝倉書店、東京(印刷中). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ming Xu: "Functional human NAIP promoter and transcriptional elements of the human NAIP and ψNAIP genes"Biochim. Biophys. Acta. 1574(1). 35-50 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takeya Okada: "Unstable transmission of the RS447 human megasatellite tandem repetitive sequence that contains the USP17 gene encoding a functional deubiquitinating enzyme"Hum. Genet.. 110(4). 302-313 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Roshni R.Singaraja: "HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis"Hum. Mol. Genet.. 11(23). 2815-2828 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 秦野伸二: "家族性ALSの新たな遺伝子"BRAIN MEDICAL. 14(1). 47-54 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 秦野伸二: "ALSの原因遺伝子"生化学. 74(6). 483-489 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 秦野伸二: "筋萎縮性側索硬化症原因遺伝子の同定とゲノム研究"ゲノム医学. 2(3). 231-240 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 秦野伸二 (分担著): "脳機能の解明-生命科学の主潮流-(赤池紀扶、東英穂、阿部康二、久保千春編)、第8章神経変性疾患の遺伝子異常と病態解明、家族性筋萎縮性側索硬化症2型(ALS2)の原因遺伝子"ガイア出版会、福岡. 299-305 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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