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Elucidation of the pathomechanism of neurodegeneration induced by TDP-43

Research Project

Project/Area Number 15K08297
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pathological medical chemistry
Research InstitutionThe University of Tokyo

Principal Investigator

Hashimoto Tadafumi  東京大学, 大学院医学系研究科(医学部), 特任准教授 (30334337)

Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords筋萎縮性側索硬化症 / 前頭側頭葉変性症 / TDP-43 / 神経変性疾患 / オートファジー / 神経変性 / ALS / 前頭側頭型認知症
Outline of Final Research Achievements

To elucidate the pathomechanism of TDP-43, we carried out RNA-seq analysis and found that Atg1 and several authophgic geneswere upregulated in the brain of TDP-43 transgenic (tg) fly. Knockdown of Atg1 rescued the retinal degeneration of TDP-43 tg fly, suggesting that autophagic pathway is involved in the pathogenesis of TDP-43. Moreover, we found that TDP-43 specifically intedacted with ULK1 mRNA in Neuro-2a cells and that knockdown of TDP-43 reduced the expression level of ULK1 protein, suggesting that TDP-43 regulates autophagic pathway via regulating the expression of ULK1.
By the analysis of the ALS-related genes, we found that overexpression of CREST induced neurodegeneration in the retina of tg fly, that familial ALS-linked mutations in Profilin1 cause the neurodegenetaion through the sequestration of TDP-43 into cytoplasm, and that self-assembly of FUS via its lox-complexity domain contributes neurodegeneration induced by FUS.

Report

(4 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (19 results)

All 2018 2017 2016 2015 Other

All Journal Article (7 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 7 results,  Open Access: 5 results,  Acknowledgement Compliant: 2 results) Presentation (11 results) (of which Int'l Joint Research: 8 results) Remarks (1 results)

  • [Journal Article] Self-assembly of FUS through its low-complexity domain contributes to neurodegeneration.2018

    • Author(s)
      Taisei Matsumoto, Koji Matsukawa, Naruaki Watanabe, Yuya Kishino, Hayato Kunugi, Ryoko Ihara, Tomoko Wakabayashi, Tadafumi Hashimoto, Takeshi Iwatsubo
    • Journal Title

      Human Molecular Genetics

      Volume: 印刷中 Issue: 8 Pages: 1353-1365

    • DOI

      10.1093/hmg/ddy046

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Soluble oligomeric amyloid-beta induces calcium dyshomeostasis that precedes synapse loss in the living mouse brain.2017

    • Author(s)
      Michal Arbel-Ornath, Eloise Hudry, Josiah R Bovine, Tadafumi Hashimoto, Shuko Takeda, Kishore V Kuchbhotla, Steven Hou, Carli R Lattarulo, Arianna M Belcher, Naomi Shakerdge, Pariss B Trujillo, Alona Muzikansky, Rebecca A Betensky, Bradley T Hyman, and Brian J Bacskai
    • Journal Title

      Molecular Neurodegeneration

      Volume: 12 Issue: 1 Pages: 27-27

    • DOI

      10.1186/s13024-017-0169-9

    • Related Report
      2017 Annual Research Report 2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer’s disease2017

    • Author(s)
      Mano Tatsuo、Nagata Kenichi、Nonaka Takashi、Tarutani Airi、Imamura Tomohiro、Hashimoto Tadafumi、Bannai Taro、Koshi-Mano Kagari、Tsuchida Takeyuki、Ohtomo Ryo、Takahashi-Fujigasaki Junko、Yamashita Satoshi、Ohyagi Yasumasa、Yamasaki Ryo、Tsuji Shoji、Tamaoka Akira、et al.
    • Journal Title

      Proc Natl Acad Sci U.S.A.

      Volume: 114 Issue: 45

    • DOI

      10.1073/pnas.1707151114

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Familial Amyotrophic Lateral Sclerosis-linked Mutations in Profilin 1 Exacerbate TDP-43-induced Degeneration in the Retina of Drosophila melanogaster through an Increase in the Cytoplasmic Localization of TDP-43.2016

    • Author(s)
      Matsukawa K, Hashimoto T, Matsumoto T, Ihara R, Chihara T, Miura M, Wakabayashi T, Iwatsubo T.
    • Journal Title

      J Biol Chem

      Volume: 291 Issue: 45 Pages: 23464-23476

    • DOI

      10.1074/jbc.m116.729152

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Calcium-responsive transactivator (CREST) protein shares a set of structural and functional traits with other proteins associated with amyotrophic lateral sclerosis2015

    • Author(s)
      Michail S. Kukharsky, Annamaria Quintiero, Taisei Matsumoto, Koji Matsukawa, Haiyan An, Tadafumi Hashimoto, Takeshi Iwatsubo, Vladimir L. Buchman, Tatyana A. Shelkovnikova
    • Journal Title

      Molecular Neurodegeneration

      Volume: 10 Issue: 1

    • DOI

      10.1186/s13024-015-0014-y

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Chronic optogenetic activation augments Aβ pathology in a mouse model of Alzheimer disease2015

    • Author(s)
      Kaoru Yamamoto, Zen-ichi Tanei, Tadafumi Hashimoto, Tomoko Wakabayashi, Hiroyuki Okuno, Yasushi Naka, Ofer Yizhar, Lief E. Fenno, Masashi Fukayama, Haruhiko Bito, John R. Cirrito, David M. Holtzman, Karl Deisseroth, Takeshi Iwatsubo
    • Journal Title

      Cell reports

      Volume: 11 Issue: 6 Pages: 859-865

    • DOI

      10.1016/j.celrep.2015.04.017

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Role of apolipoprotein E in β-amyloidgenesis: isoform-specific effects on protofibril to fibril conversion of Aβ in vitro and brain Aβ deposition in vivo.2015

    • Author(s)
      Yukiko Hori, Tadafumi Hashimoto, Hidetoshi Nomoto, Bradley T Hyman, Takeshi Iwatsubo
    • Journal Title

      Journal of Biological Chemistry

      Volume: 290 Issue: 24 Pages: 15163-15174

    • DOI

      10.1074/jbc.m114.622209

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Characterization of the high molecular weight Abeta oligomers derived from the brains of APP transgenic mice2017

    • Author(s)
      Tadafumi Hashimoto, Yasushi Naka, Tomoya Tajiri, Mayu Hakozaki-Kashiwagi, Takeshi Iwatsubo
    • Organizer
      Neuroscience2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Differential effects of human and mouse apolipoprotein E on the metabolism and aggregation of amyloid-beta peptides2017

    • Author(s)
      Asuka Kokawa, Yutaro Ohno, Tadafumi Hashimoto, Takeshi Iwatsubo
    • Organizer
      Neuroscience2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The relationship between insulin resistance and amyloid pathology in diabetic AD model mice2017

    • Author(s)
      K Matsui, K Yamaguchi, A Mano, T Sano, T Hashimoto, T Kubota, T Kadowaki, T Wakabayashi, T Iwatsubo
    • Organizer
      Neuroscience2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Casein kinase 1 delta/ipsilon がFUSの神経毒性に与える影響に関する検討2017

    • Author(s)
      岸野祐也、松川浩二、野中隆、松本大成、長谷川成人、橋本唯史、岩坪威
    • Organizer
      第36回日本認知症学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] TDP-43はAtg1/ULK1のプロセシング異常を介して神経変性を引き起こす2016

    • Author(s)
      松川浩二、岸野祐也、若林朋子、橋本唯史、岩坪威
    • Organizer
      第35回日本認知症学会
    • Place of Presentation
      東京国際フォーラム(東京都千代田区)
    • Year and Date
      2016-12-01
    • Related Report
      2016 Research-status Report
  • [Presentation] ヒトapoEがAβの脳内dynamicsに与える影響の解明2016

    • Author(s)
      粉川明日香、大野裕太郎、橋本唯史、岩坪威
    • Organizer
      第35回日本認知症学会
    • Place of Presentation
      東京国際フォーラム(東京都千代田区)
    • Year and Date
      2016-12-01
    • Related Report
      2016 Research-status Report
  • [Presentation] Novel cellular and in vivo models for intercellular transmission of FUS2016

    • Author(s)
      Tadafumi Hashimoto, Taisei Matsumoto, Koji Matsukawa, Naruaki Watanabe, Tomoko Wakabayashi, Takeshi Iwatsubo
    • Organizer
      Gordon Research Conferences. Neurobiology of brain disorders
    • Place of Presentation
      Girona, Spain
    • Year and Date
      2016-08-07
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Development of a novel cell-based model for oligomerization and intercellular transmission of FUS2016

    • Author(s)
      Tadafumi Hashimoto, Taisei Matsumoto, Koji Matsukawa, Naruaki Watanabe, Tomoko Wakabayashi, Takeshi Iwatsubo
    • Organizer
      Neuroscience 2016
    • Place of Presentation
      San Diego, USA
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Roles of Ab plaques on the dynamics of soluble Ab in the brains of APP transgenic mice.2016

    • Author(s)
      Yasushi Naka, Tomoko Wanabayashi, Tadafumi Hashimoto, Takeshi Iwatsubo
    • Organizer
      Neuroscience 2016
    • Place of Presentation
      San Diego, USA
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] CLAC alters the morphology and dynamics of amyloid-β peptides in the brain2015

    • Author(s)
      Tadafumi Hashimoto, Yasushi Naka, Daisuke Fujii, Mayu Kashiwagi, Tomoko Wakabayashi, Takeshi Iwatsubo
    • Organizer
      Neuroscience 2015
    • Place of Presentation
      Chicago, USA
    • Year and Date
      2015-10-17
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] Self-assembly of FUS is required for the degeneration of retinal photoreceptor neurons in transgenic Drosophila melanogaster overexpressing human FUS2015

    • Author(s)
      Tadafumi Hashimoto, Taisei Matsumoto, Hayato Kunugi, Koji Matsukawa, Tomoko Wakabayashi, Takeshi Iwatsubo
    • Organizer
      10th Brain Research Conference
    • Place of Presentation
      Chicago, USA
    • Year and Date
      2015-10-15
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Remarks] 東京大学大学院医学系研究科神経病理学分野ホームページ

    • URL

      http://www.neuropathology.m.u-tokyo.ac.jp/news.html#MatsukawaJBC2016

    • Related Report
      2016 Research-status Report

URL: 

Published: 2015-04-16   Modified: 2019-03-29  

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