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Research on Pathomechanisms of Brain Disorders

Research Project

Project/Area Number 16071101
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionThe Institute of Physical and Chemical Research

Principal Investigator

NUKINA Nobuyuki  独立行政法人理化学研究所, 構造神経病理研究チーム, チームリーダー (10134595)

Co-Investigator(Kenkyū-buntansha) 岩坪 威  東京大学, 大学院・医学系研究科, 教授 (50223409)
井原 康夫  同志社大学, 生命医科学部設置凖備室, 教授 (60114386)
祖父江 元  名古屋大学, 大学院・医学系研究科, 教授 (20148315)
西川 徹  東京医科歯科大学, 大学院・医歯学総合研究科, 教授 (00198441)
Co-Investigator(Renkei-kenkyūsha) IWATSUBO Takeshi  東京大学, 大学院・薬学系研究科, 教授 (50223409)
IHARA Yasuo  同志社大学, 生命医科学部・設置準備室, 教授 (60114386)
SOFUE Gen  名古屋大学, 大学院・医学系研究科, 教授 (20148315)
NISHIKAWA Toru  東京医科歯科大学, 大学院・医歯学総合研究科, 教授 (00198441)
Project Period (FY) 2004 – 2010
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥27,000,000 (Direct Cost: ¥27,000,000)
Fiscal Year 2010: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2009: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2008: ¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2007: ¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2006: ¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2005: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2004: ¥3,500,000 (Direct Cost: ¥3,500,000)
Keywords統合脳 / 病態脳 / 脳科学 / 神経疾患 / 変性疾患 / 精神疾患
Research Abstract

「病態脳」の研究期間において学問領域を新たに展開し得た業績としては前頭側頭葉認知症や筋萎縮性側索硬化症ALSの病態関連分子としてのTDP-43の同定である。本研究班はこれに貢献するとともにALS関連分子として同定されたFUS/TLSの機能解析において先駆的な研究を展開し、またALSにおけるRNA editing病態の解析といった世界的にもユニークな研究を展開した。また神経変性疾患におけるタンパク質分解系の役割としてオートファジーの研究を展開し、その治療応用などの方向性も示した。アルツハイマー病やパーキンソン病の病態の基礎研究を進展させるとともにさまざまなモデル動物も作製できた。精神疾患においてはゲノム異常と関連する研究において先端的な研究を行い、新たな精神発達遅滞遺伝子の同定や一部の統合失調症の家系解析から新たな病態仮説を提唱した。またゲノム工学を用いた自閉症マウスモデルの作製にも成功した。さらにこれらの疾患関連遺伝子の遺伝子導入やノックアウトにより作製されたモデルマウスの行動異常解析が系統的に行われるようになり、今後の研究展開の基盤ができた。これらの研究の成果の一部はすでにNature, Nat Cell Biol, Nat Biotech Nat Struct Mol Biol, Cell等の一流国際誌やJ. Neurosci, Biol Psychiatryといった一流専門誌に多く発表され、これらを含む約1700編の英文論文が発表された。
「統合脳」の一翼として活動することにより、病態脳科学という領域を形成し、今後の統合的脳疾患研究の基盤を形成することが出来た。またこれらの成果を一般に向け公開するとともに、「包括脳」として今後より広く研究支援活動を行うことも可能となった。本年度は5年間の「病態脳」研究成果をまとめ、冊子およびCDとして報告書を作成し、領域内外に公開した。

Report

(8 results)
  • 2010 Annual Research Report
  • 2009 Annual Research Report   Final Research Report ( PDF )
  • 2008 Annual Research Report
  • 2007 Annual Research Report
  • 2006 Annual Research Report
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • Research Products

    (34 results)

All 2010 2009 2008 2007 2006 2005 2004 Other

All Journal Article (31 results) (of which Peer Reviewed: 14 results) Remarks (3 results)

  • [Journal Article] Intracellular localization and splicing regulation of FUS/TLS are variably affected by amyotrophic lateral sclerosis-linked mutations.2010

    • Author(s)
      Kino, Y., et al.
    • Journal Title

      Nucleic Acids Res.

      Volume: (in press)

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Harnessing chaperone-mediated autophagy for the selective degradation of mutant huntingtin protein.2010

    • Author(s)
      Bauer, P.O., et al.
    • Journal Title

      Nat.Biotechnol.

      Volume: 28 Pages: 256-263

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mutant huntingtin fragment selectively suppresses Brn-2 POU domain transcription factor to mediate hypothalamic cell dysfunction.2010

    • Author(s)
      Yamanaka, T., et al.
    • Journal Title

      Hum.Mol.Genet.

      Volume: 19 Pages: 2099-2112

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cross-seeding fibrillation of Q/N-rich proteins offers new pathomechanism of polyglutamine diseases2009

    • Author(s)
      Furukawa, Y., et al.
    • Journal Title

      J.Neurosci. 29

      Pages: 5153-5162

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Identification of the autophosphorylation sites of LRRK22009

    • Author(s)
      Kamikawaji, S.et al.
    • Journal Title

      Biochemistry 48

      Pages: 10963-10975

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Blocking acid-sensing ion channel 1 alleviates Huntington's disease pathology via an ubiquitin-proteasome system-dependent mechanism.2008

    • Author(s)
      Wong, H. K., et al.
    • Journal Title

      Hum. Mol. Genet. 17

      Pages: 3223-3235

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mutant Huntingtin reduces HSP70 expression through the sequestration of NF-Y transcription factor.2008

    • Author(s)
      Yamanaka, T., et al.
    • Journal Title

      EMBO J. 27

      Pages: 827-839

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] RNA-binding protein TLS is a major nuclear aggregate-interacting protein in huntingtin exon l with expanded polyglutamine-expressing cells.2008

    • Author(s)
      Doi, H., et al.
    • Journal Title

      J. Biol. Chem. 283

      Pages: 6489-6500

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Abeta 46 is processed to Abeta 40 and Abeta43, but not to Abeta42, in the low density membrane domains.2008

    • Author(s)
      Yagishita, S., et. al.
    • Journal Title

      J Biol Chem 283

      Pages: 733-8

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CHIP overexpression reduces mutant androgen receptor protein and ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model.2007

    • Author(s)
      Adachi, H., et. al.
    • Journal Title

      J Neurosci 27

      Pages: 5115-26

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Selective serotonin reuptake inhibitors, fluoxetine and paroxetine, attenuate the expression of the established behavioral sensitization induced by methamphetamine.2007

    • Author(s)
      Kaneko, Y., et. al.
    • Journal Title

      Neuropsychopharmacology 32

      Pages: 658-64

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease.2007

    • Author(s)
      Ito, G., et. al.
    • Journal Title

      Biochemistry 46

      Pages: 1380-8

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Sodium channel beta4 subunit : down-regulation and possible involvement in neuritic degeneration in Huntington s disease transgenic mice.2006

    • Author(s)
      Oyama, F. et al.
    • Journal Title

      J Neurochem 98

      Pages: 518-529

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Dynamin-binding protein gene on chromosome 10q is associated with late-onset Alzheimer's disease.2006

    • Author(s)
      Kuwano, R. et al.
    • Journal Title

      Hum Mol Genet 15

      Pages: 2170-2182

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Reversible disruption of dynactin l-mediated retrograde axonal transport in polyglutamine-induced motor neuron degeneration.2006

    • Author(s)
      Katsuno, M. et al.
    • Journal Title

      J Neurosci 26

      Pages: 12106-12117

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Inhibition of D-serine accumulation in the Xenopus oocyte by expression of the rat ortholog of human 3' -phosphoadenosine 5' -phosphosulfate transporter gene isolated from the neocortex as D-serine modulator-1.2006

    • Author(s)
      Shimazu, D. et al.
    • Journal Title

      J Neurochem 96

      Pages: 30-42

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Structure of the catalytic pore of gamma-secretase probed by the accessibility of substituted cysteines.2006

    • Author(s)
      Sato, C. et al.
    • Journal Title

      J Neurosci 26

      Pages: 12081-12088

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Familial Parkinson mutant alpha-synuclein causes dopamine neuron dysfunction in transgenic Caenorhabditis elegans.2006

    • Author(s)
      Kuwahara, T. et al.
    • Journal Title

      J Biol Chem 281

      Pages: 334-340

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Inhibition of D-serine accumulation in the Xenopus oocyte by expression of the rat ortholog of human 3'-phosphoadenosine 5'-phosphosulfate transporter gene isolated from the neocortex as D-serine modulator-1.2006

    • Author(s)
      Shimazu, D.
    • Journal Title

      J Neurochem 96

      Pages: 30-42

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Co-chaperone CHIP associates with expanded polyglutamine protein and promotes their degradation by proteasomes.2005

    • Author(s)
      Jana, N.R.et al.
    • Journal Title

      J Biol Chem 280

      Pages: 11635-11640

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Longer forms of amyloid beta protein : implications for the mechanism of intramembrane cleavage by gamma-secretase.2005

    • Author(s)
      Qi-Takahara, Y. et al.
    • Journal Title

      J Neurosci 25

      Pages: 436-445

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease.2005

    • Author(s)
      Katsuno, M. et al.
    • Journal Title

      Proc Natl Acad Sci USA 102

      Pages: 16801-16806

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration.2005

    • Author(s)
      Waza, M. et al.
    • Journal Title

      Nat Med 11

      Pages: 1088-1095

    • Related Report
      2005 Annual Research Report
  • [Journal Article] A family-based association study and gene expression analyses of netrin-G1 and -G2 genes in schizophrenia.2005

    • Author(s)
      Aoki-Suzuki, M., et al.
    • Journal Title

      Biol Psychiatry 57

      Pages: 382-393

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins.2004

    • Author(s)
      Venkatraman, P., et al.
    • Journal Title

      Mol Cell 14, 95-104(2004). 14

      Pages: 95-104

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease.2004

    • Author(s)
      Tanaka, M., et al.
    • Journal Title

      Nat Med 10

      Pages: 148-154

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Gem GTPase and tau : morphological changes induced by gem GTPase in cho cells are antagonized by tau.2004

    • Author(s)
      Oyama, F., et al.
    • Journal Title

      J Biol Chem 279

      Pages: 27272-27277

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Sodium butyrate ameliorates phenatypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy.2004

    • Author(s)
      Minamiyama, M., et al.
    • Journal Title

      Hum Mol Genet 13

      Pages: 1183-1192

    • Related Report
      2004 Annual Research Report
  • [Journal Article] CLAC binds to amyloid beta peptides through the positively-charged amino acid cluster within the collagen domain 1 and inhibits formation of amyloid fibrils.2004

    • Author(s)
      Osada, Y., et al.
    • Journal Title

      J Biol Chem

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Novel gene therapy for polyglutamine diseases to degrade selectively the pathogenic protein

    • Author(s)
      Bauer, P.O.et al.
    • Journal Title

      Nat.Biotech. (in press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mutant Huntingtin reduces HSP70 expression through the sequestration of NF-Y transcription factor. Embo J(2008).

    • Author(s)
      Yamanaka, T., et. al.
    • Journal Title

      Embo J (in press)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Remarks]

    • URL

      http://www.togo-nou.nips.ac.jp/

    • Related Report
      2009 Final Research Report
  • [Remarks]

    • URL

      http://www.togo-nou.nips.ac.jp/

    • Related Report
      2009 Annual Research Report
  • [Remarks]

    • URL

      http://www.togo-nou.nips.ac.jp/

    • Related Report
      2008 Annual Research Report

URL: 

Published: 2004-04-01   Modified: 2018-08-07  

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