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蛋白質老化におけるRab活性制御の分子機構の解析

Publicly Offered Research

Project AreaPrevention of brain protein aging and dementia
Project/Area Number 17H05682
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionTohoku University

Principal Investigator

福田 光則  東北大学, 生命科学研究科, 教授 (50311361)

Project Period (FY) 2017-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000)
Fiscal Year 2018: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2017: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Keywords低分子量Gタンパク質Rab / ALS/FTD / 膜輸送 / Rab panel / スクリーニング / Rabエフェクター / ALS2 / C9ORF72 / 低分子量G蛋白質Rab / グアニンヌクレオチド交換因子 / ALS / 神経疾患 / エキソソーム
Outline of Annual Research Achievements

低分子量Gタンパク質Rabは小胞輸送(膜輸送)の普遍的制御因子であり、その名前の由来通り、特に脳組織での発現が高い。これまでRabやその制御因子の変異により20種類を超えるヒトやマウスの遺伝病が報告されており、その多くが神経疾患の症状を呈する。しかし、これらの分子がどのような小胞輸送経路に関与し、神経機能を制御しているかは未だ不明な点が多い。本研究では、筋萎縮性側索硬化症(ALS)の原因遺伝子産物の一つであるALS2が、Rab活性化に関わるVps9ドメインを含むことに着目し、ALS2の基質Rabの同定と神経機能におけるRab活性化の意義の解明を目指した。これまでの解析で、ALS2が既知の基質であるRab5に加え、Rab17の活性化にも関与することを明らかにし、それらのノックダウンにより海馬神経細胞の神経突起の伸長や形態形成が阻害されることを見出している。また、ALS2と候補Rabのノックアウト細胞株の作製にも取り組み、Rab5が細胞の増殖・生存に必須であることを明らかにした。ALS2をノックアウトしたSH-SY5Y細胞(ヒト神経芽細胞腫)では増殖能が著しく損なわれたが、HeLa細胞のノックアウトでは特に影響が見られなかったことから、ALS2は特定の細胞種(例えば、特定の神経細胞)でRab5の活性化を通して細胞外からの物質の取り込み(マクロピノサイトーシスなど)に関与し、細胞の生存に必須の役割を果たすことが強く示唆される。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (38 results)

All 2019 2018 2017 Other

All Int'l Joint Research (3 results) Journal Article (15 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 15 results,  Open Access: 9 results) Presentation (19 results) (of which Int'l Joint Research: 5 results,  Invited: 4 results) Remarks (1 results)

  • [Int'l Joint Research] Pasteur Institute(フランス)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] University of Oxford(英国)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] Augusta University(米国)

    • Related Report
      2017 Annual Research Report
  • [Journal Article] Rab10 regulates tubular endosome formation through KIF13A and KIF13B motors.2019

    • Author(s)
      Etoh, K. and Fukuda, M.
    • Journal Title

      J. Cell Sci.

      Volume: 132

    • DOI

      10.1242/jcs.226977

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cytoplasmic control of Rab family small GTPases through BAG62019

    • Author(s)
      Takahashi Toshiki、Minami Setsuya、Tsuchiya Yugo、Tajima Kazu、Sakai Natsumi、Suga Kei、Hisanaga Shin‐ichi、Ohbayashi Norihiko、Fukuda Mitsunori、Kawahara Hiroyuki
    • Journal Title

      EMBO reports

      Volume: 20 Issue: 4

    • DOI

      10.15252/embr.201846794

    • NAID

      120007127921

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The BLOC-3 subunit HPS4 is required for activation of Rab32/38 GTPases in melanogenesis, but its Rab9 activity is dispensable for melanogenesis.2019

    • Author(s)
      Ohishi, Y., Kinoshita, R., Marubashi, S., Ishida, M. and Fukuda, M.
    • Journal Title

      J. Biol. Chem.

      Volume: 294 Issue: 17 Pages: 6912-6922

    • DOI

      10.1074/jbc.ra119.007345

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Rab7 knockout unveiled regulated autolysosome maturation induced by glutamine starvation2018

    • Author(s)
      Kuchitsu Y, Homma Y, Fujita N, Fukuda M
    • Journal Title

      Journal of Cell Science

      Volume: 印刷中 Issue: 7

    • DOI

      10.1242/jcs.215442

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Molecular mechanisms of Streptococcus pneumoniae-targeted autophagy via pneumolysin, Golgi-resident Rab41, and Nedd4-1-mediated K63-linked ubiquitination2018

    • Author(s)
      Ogawa M, Matsuda R, Takada N, Tomokiyo M, Yamamoto S, Shizukusihi S, Yamaji T, Yoshikawa Y, Yoshida M, Tanida I, Koike M, Murai M, Morita H, Takeyama H, Ryo A, Guan JL, Yamamoto M, Inoue JI, Yanagawa T, Fukuda M, Kawabe H, Ohnishi M
    • Journal Title

      Cellular Microbiology

      Volume: e12846 Issue: 8

    • DOI

      10.1111/cmi.12846

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis2018

    • Author(s)
      Eguchi Tomoya、Kuwahara Tomoki、Sakurai Maria、Komori Tadayuki、Fujimoto Tetta、Ito Genta、Yoshimura Shin-ichiro、Harada Akihiro、Fukuda Mitsunori、Koike Masato、Iwatsubo Takeshi
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 115 Issue: 39

    • DOI

      10.1073/pnas.1812196115

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Rab11a-Rab8a cascade regulate the formation of tunneling nanotubes through vesicle recycling.2018

    • Author(s)
      Zhu, S., Bhat, S., Syan, S., Kuchitsu, Y., Fukuda, M. and Zurzolo, C.
    • Journal Title

      J. Cell Sci.

      Volume: 131

    • DOI

      10.1242/jcs.215889

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Revisiting Rab7 functions in mammalian autophagy: Rab7 knockout studies.2018

    • Author(s)
      Kuchitsu, Y. and Fukuda, M.
    • Journal Title

      Cells

      Volume: 7 Issue: 11 Pages: 215-215

    • DOI

      10.3390/cells7110215

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Rab5 activation on macropinosomes requires ALS2, and subsequent Rab5 inactivation through ALS2 detachment requires active Rab7.2018

    • Author(s)
      Morishita S, Wada N, Fukuda M, Nakamura T.
    • Journal Title

      FEBS Letter

      Volume: 593 Issue: 2 Pages: 230-241

    • DOI

      10.1002/1873-3468.13306

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Rab20, a novel Rab small GTPase that negatively regulates neurite outgrowth of PC12 cells.2018

    • Author(s)
      Oguchi, M. E., Etoh, K. and Fukuda, M.
    • Journal Title

      Neurosci. Lett.

      Volume: 662 Pages: 324-330

    • DOI

      10.1016/j.neulet.2017.10.056

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Parkinson’s disease-linked DNAJC13 mutation aggravates α-synuclein-induced neurotoxicity through perturbation of endosomal trafficking.2018

    • Author(s)
      Yoshida S, Hasegawa T, Suzuki M, Sugeno N, Kobayashi J, Ueyama M, Fukuda M, Ido-Fujibayashi A, Sekiguchi K, Ezura M, Kikuchi A, Baba T, Takeda A, Mochizuki H, Nagai Y and Aoki M.
    • Journal Title

      Hum Mol Genet.

      Volume: 27 Issue: 5 Pages: 823-836

    • DOI

      10.1093/hmg/ddy003

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] C9orf72 and RAB7L1 regulate vesicle trafficking in amyotrophic lateral sclerosis and frontotemporal dementia.2017

    • Author(s)
      Aoki, Y., Manzano, R., Lee, Y., Dafinca, R., Aoki, M., Douglas, A. G. L., Varela, M. A., Sathyaprakash, C., Scaber, J., Barbagallo, P., Vader, P., Mager, I., Ezzat, K., Turner, M. R., Ito, N., Gasco, S., Ohbayashi, N., El-Andaloussi, S., Takeda, S., Fukuda, M., Talbot, K. and Wood, M. J. A.
    • Journal Title

      Brain

      Volume: 140 Issue: 4 Pages: 887-897

    • DOI

      10.1093/brain/awx024

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] TBC1D12 is a novel Rab11-binding protein that modulates neurite outgrowth of PC12 cells.2017

    • Author(s)
      Oguchi, M. E., Noguchi, K. and Fukuda, M.
    • Journal Title

      PLoS One

      Volume: 12 Issue: 4 Pages: e0174883-e0174883

    • DOI

      10.1371/journal.pone.0174883

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The RAB2B-GARIL5 Complex Promotes Cytosolic DNA-Induced Innate Immune Responses2017

    • Author(s)
      Takahama Michihiro、Fukuda Mitsunori、Ohbayashi Norihiko、Kozaki Tatsuya、Misawa Takuma、Okamoto Toru、Matsuura Yoshiharu、Akira Shizuo、Saitoh Tatsuya
    • Journal Title

      Cell Reports

      Volume: 20 Issue: 12 Pages: 2944-2954

    • DOI

      10.1016/j.celrep.2017.08.085

    • NAID

      120007134819

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The GTPase Rab43 controls the anterograde ER-Golgi trafficking and sorting of GPCRs.2017

    • Author(s)
      Li, C., Wei, Z., Fan, Y., Huang, W., Su, Y., Li, H., Dong, Z., Fukuda, M., Khater, M. and Wu, G.
    • Journal Title

      Cell Rep.

      Volume: 21 Issue: 4 Pages: 1089-1101

    • DOI

      10.1016/j.celrep.2017.10.011

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] グルタミン飢餓により誘導されるオートリソソームの成熟現象の発見2018

    • Author(s)
      朽津芳彦、本間悠太、藤田尚信、福田光則
    • Organizer
      日本生化学会東北支部 第84回例会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 筋細胞の再構成に伴い形成される管状リソソームの形成機構2018

    • Author(s)
      村川直柔、福田光則、藤田尚信
    • Organizer
      日本生化学会東北支部 第84回例会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 神経ネットワークにおける低分子量GTPase Rabの役割:Rabの機能不全と神経変性2018

    • Author(s)
      福田光則
    • Organizer
      第59回日本神経学会学術大会シンポジウム“How neurons keep calm and carry on: roles of quality control in neurodegenerative diseases”
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Rab7 knockout unveiled regulated autolysosome maturation induced by glutamine starvation.2018

    • Author(s)
      朽津芳彦、本間悠太、藤田尚信、福田光則
    • Organizer
      第70回日本細胞生物学会大会・第51回発生生物学会合同大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] The small GTPase Rab10 regulates the formation of tubular endosomes through its novel effectors KIF13A/B.2018

    • Author(s)
      衛藤貫、福田光則
    • Organizer
      第70回日本細胞生物学会大会・第51回発生生物学会合同大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Rab knockout projects unveil new insight into functions of Rabs in membrane traffic.2018

    • Author(s)
      福田光則
    • Organizer
      第70回日本細胞生物学会大会・第51回発生生物学会合同大会シンポジウム「オルガネラバイオロジー・リローディッド」
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] ショウジョウバエを用いた筋細胞特異的なオルガネラ形成機構の解析2018

    • Author(s)
      村川直柔、福田光則、藤田尚信
    • Organizer
      日本筋学会第4回学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] グルタミン飢餓によりオートリソソームの成熟が促進される現象の発見2018

    • Author(s)
      朽津芳彦、本間悠太、藤田尚信、福田光則
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 筋細胞リモデリングに伴い形成される管状リソソームネットワークのダイナミクスの解析2018

    • Author(s)
      村川直柔、福田光則、藤田尚信
    • Organizer
      第11回オートファジー研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 筋細胞に見られるオートファジー依存的な管状リソソームネットワーク2018

    • Author(s)
      藤田尚信、村川直柔、福田光則
    • Organizer
      第11回オートファジー研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Role of Rab small GTPases in neurite outgrowth and differentiation.2018

    • Author(s)
      Mitsunori Fukuda
    • Organizer
      A symposium in honor of Sumiko Mochida “Forefront of Neurotransmitter Release and Calcium Channel Signaling”
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Autolysosome maturation induced by glutamine starvation.2018

    • Author(s)
      Yoshihiko Kuchitsu and Mitsunori Fukuda
    • Organizer
      Neoprotein biology - From synthesis to trafficking
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Comprehensive knockout analysis of the Rab family small GTPases in MDCK cells.2018

    • Author(s)
      Yuta Homma, Riko Kinoshita, Yoshihiko Kuchitsu, Paulina S. Wawro, Soujiro Marubashi, Mai E. Oguchi, Morie Ishida, Naonobu Fujita and Mitsunori Fukuda
    • Organizer
      The 2018 ASCB/EMBO meeting
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] リサイクリングエンドソームに局在する新規 Rab11 結合タンパク質TBC1D12 は神経突起伸長を制御する2017

    • Author(s)
      小口舞、野口憲太、福田光則
    • Organizer
      日本生化学会東北支部 第83回例会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 神経突起伸長を負に制御する新規低分子量Gタンパク質Rabの探索2017

    • Author(s)
      小口舞、衛藤貫、福田光則
    • Organizer
      第69回日本細胞生物学会大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 変異DNAJC13はエンドソーム輸送障害を介してαシヌクレイン神経毒性を増強する2017

    • Author(s)
      長谷川隆文、吉田隼、鈴木マリ、菅野直人、小林潤平、福田光則、藤林明美、関口清俊、江面道典、菊池昭夫、武田篤、望月秀樹、永井義隆、青木正志
    • Organizer
      第40回日本神経科学大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] ALS2結合タンパク質Rab30は、神経細胞においてエンドソームゴルジ体間の輸送に関与する2017

    • Author(s)
      大友麻子、松井香奈、小野寺和歌奈、杉山純也、石田智之、白川涼平、佐藤海、三井駿、野崎昌久、小野鈴花、福田光則、秦野伸二
    • Organizer
      第40回日本神経科学大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Rab small GTPases are key players for neurite outgrowth and differentiation.2017

    • Author(s)
      Mitsunori Fukuda
    • Organizer
      Seminar in the National Center of Neurology and Psychiatry
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] C9ORF72 is a novel Rab7L1/29-binding protein that regulates intracellular membrane traffic.2017

    • Author(s)
      Mitsunori Fukuda and Yoshitsugu Aoki
    • Organizer
      The 2nd International Symposium of “Brain Protein Aging and Dementia Control”
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Remarks] 東北大学大学院生命科学研究科膜輸送機構解析分野

    • URL

      https://www.lifesci.tohoku.ac.jp/research/teacher/detail.html?id=1724

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report

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Published: 2017-04-28   Modified: 2022-02-28  

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