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Molecular pathogenesis of Parkinson's disease

Research Project

Project/Area Number 17025009
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionThe University of Tokyo

Principal Investigator

IWATSUBO Takeshi  The University of Tokyo, 大学院・医学系研究科, 教授 (50223409)

Project Period (FY) 2005 – 2009
Project Status Completed (Fiscal Year 2009)
Budget Amount *help
¥161,100,000 (Direct Cost: ¥161,100,000)
Fiscal Year 2009: ¥33,400,000 (Direct Cost: ¥33,400,000)
Fiscal Year 2008: ¥33,000,000 (Direct Cost: ¥33,000,000)
Fiscal Year 2007: ¥31,000,000 (Direct Cost: ¥31,000,000)
Fiscal Year 2006: ¥31,000,000 (Direct Cost: ¥31,000,000)
Fiscal Year 2005: ¥32,700,000 (Direct Cost: ¥32,700,000)
Keywordsパーキンソン病 / αシヌクレイン / LRRK2 / 神経変性 / リン酸化 / キナーゼ活性 / 遺伝子 / プロテインキナーゼ / 脳神経疾患 / 老化 / 神経化学
Research Abstract

Using transgenic C. elegans that pan-neuronally overexpress human alpha-synuclein in neurons, we searched for genes that modify the neurotoxicity of alpha-synuclein, and identified endocytosis-related genes as modifiers. These results suggest that impairment in endocytotic function is involved in the mechanism of neurodegeneration of PD. We also found that GTP binding is essential to the kinase activity of LRRK2, a responsible gene product of PARK8. We also found that autophosphorylation of Thr1410 and Thr1967 of LRRK2 is important for the regulation of its kinase activity.

Report

(6 results)
  • 2009 Annual Research Report   Final Research Report ( PDF )
  • 2008 Annual Research Report
  • 2007 Annual Research Report
  • 2006 Annual Research Report
  • 2005 Annual Research Report
  • Research Products

    (29 results)

All 2009 2008 2007 2006 2005

All Journal Article (23 results) (of which Peer Reviewed: 17 results) Presentation (6 results)

  • [Journal Article] Identification of the autophosphorylation sites of LRRK2 linked to familial Parkinson's disease.2009

    • Author(s)
      Kamikawaji, S., Ito, G., Iwatsubo, T.
    • Journal Title

      Biochemistry 48

      Pages: 10963-10975

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

    • Author(s)
      Kamikawaji S, Ito G, iwatsubo T
    • Journal Title

      Biochemistry 48

      Pages: 10963-10975

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A large-scale RNA interference screen identifies endocytic pathway genes as modifiers of α-synuclein toxicity in transgenic Caenorhabditis elegans.2008

    • Author(s)
      Kuwahara, T, Koyama A., Koyama, S., Yoshina, S., Ren, C. -H., Kato, T., Mitani, S., Iwatsubo, T.
    • Journal Title

      Human Molecular Genetics 17 17

      Pages: 2997-3009

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] A large-scale RNA interference screen identifies endocytic pathway genes as m odifiers of asynuclein toxicity in transgenic Caenorhabditis elegans2008

    • Author(s)
      Kuwahara T, Koyama A, Koyama S, Yoshina S, Ren C-H, Kato T, M itani S, Iwatsubo T
    • Journal Title

      Human Molecular Genetics 17

      Pages: 2997-3009

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Relationship of phosphorylated asynuclein and tau accumulation to Aβ deposit ion in the cerebral cortex of dementia with Lewy bodies2008

    • Author(s)
      Obi, K Akiyama H, Kondo H, Shi momura Y, Hasegawa M, Iwatsubo T. Mizuno Y, Mochizuki H
    • Journal Title

      Exp Neurol 210

      Pages: 409-420

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hsp104 antagonizes asynuclein aggregation and reduces dopaminergic degenera tion in a rat model of Parkinson's disease2008

    • Author(s)
      Lo Bianco C, James Shorter C, Re gulier E, Lashuel H, Iwatsubo T, L indquist S, Aebischer P
    • Journal Title

      J Clin Invest 118

      Pages: 3087-3097

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cytoplasmic localization and proteasomal degradation of N-terminally cleaved form of PINK12008

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

      Neurosci Lett 430

      Pages: 13-17

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Selective loss of nigral dopamine neurons induced by overexpression of truncated human α-synuclein in mice.2008

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

      Neurobiol Aging 29

      Pages: 574-585

    • 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., Okai, T., Fujino, G., Takeda, K., Ichijo, H., Katada, T., Iwatsubo, T.
    • Journal Title

      Biochemistry 46

      Pages: 1380-1388

    • Related Report
      2009 Final 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: 1380-1388

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Analysis of adrenal gland is useful for evaluating pathology of the peripheral autonomic nervous system in Lewy body disease.2007

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

      J Neuropathol Exp Neurol 66

      Pages: 354-362

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

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

      Biochemistry 46

      Pages: 354-362

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Correlation in Lewy pathology between the claustrum and visual areas in brains of dementia with Lewy bodies.2007

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

      Neurosci Lett 415

      Pages: 219-224

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Casein kinase 2 is the major enzyme in brain that phosphorylates Ser129 of human α-synuclein: Implication for α-synucleinopathies.2007

    • Author(s)
      Ishii A, et. al.
    • Journal Title

      FEBS letters 581

      Pages: 4711-4717

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 920 MHz ultra-high field NMR studies of antibody binding and site-specific phosphorylation of α-synuclein.2007

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

      Biochem Biophys Res Comm 363

      Pages: 795-799

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Enhanced accumulation of phosphorylated α-synuclein and elevated Aβ42/40 ratio caused by expression of the presenilin-1 ΔT440 mutant associated with familial Lewy body disease and variant Alzheimer disease.2007

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

      J Neuroscience 27

      Pages: 13092-13013

    • 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
    • Journal Title

      Biochemistry 46

      Pages: 1380-1388

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

    • Author(s)
      Kuwahara, T., Koyama, A., Gengyo-Ando, K., Masuda, M., Kowa, H., Tsunoda, M., Mitani, S., Iwatsubo, T.
    • Journal Title

      J. Biol. Chem. 281

      Pages: 334-340

    • Related Report
      2009 Final Research Report
    • Peer Reviewed
  • [Journal Article] The role of G protein-coupled receptor kinase 5 in pathogenesis of sporadic Parkinson's disease.2006

    • Author(s)
      Arawaka S
    • Journal Title

      J Neuroscience 26

      Pages: 9227-9238

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Small molecule inhibitors of α-synuclein filament assembly.2006

    • Author(s)
      Masuda M
    • Journal Title

      Biochemistry 45

      Pages: 6084-6095

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

    • Author(s)
      Kuwahara T
    • Journal Title

      J Biol Chem 281

      Pages: 334-340

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Roles of distinct cysteine residues in S-nitrosylation and dimerization of DJ-1.2006

    • Author(s)
      Ito G
    • Journal Title

      Biochem Biophys Res Comm 339

      Pages: 667-672

    • Related Report
      2005 Annual Research Report
  • [Journal Article] α-Synuclein phosphorylation enhances Lewy body-like inclusion formation in SH-SY5Y cells.2005

    • Author(s)
      Smith WW
    • Journal Title

      J Neurosci 25

      Pages: 5544-5552

    • Related Report
      2005 Annual Research Report
  • [Presentation] パーキンソン病の分子病態―αシヌクレインとLRRK2をめぐって2009

    • Author(s)
      岩坪威
    • Organizer
      第7回パーキンソン病懇話会
    • Place of Presentation
      アークホテル岡山(岡山県)
    • Year and Date
      2009-11-05
    • Related Report
      2009 Annual Research Report
  • [Presentation] Normal and pathological function of LRRK22008

    • Author(s)
      Iwatsubo T
    • Organizer
      12th International Congress of Parkinson's Disease and Movement Disorders
    • Place of Presentation
      Chicago, USA
    • Year and Date
      2008-06-26
    • Related Report
      2008 Annual Research Report
  • [Presentation] DLBの分子遺伝2007

    • Author(s)
      Iwatsubo T
    • Organizer
      第1回DLB研究会
    • Place of Presentation
      横浜
    • Year and Date
      2007-11-10
    • Related Report
      2007 Annual Research Report
  • [Presentation] パーキンソン病の分子病態:α-synucleinとLRRK2をめぐって2007

    • Author(s)
      Iwatsubo T
    • Organizer
      第12回東海パーキンソン病研究会
    • Place of Presentation
      名古屋
    • Year and Date
      2007-09-28
    • Related Report
      2007 Annual Research Report
  • [Presentation] パーキンソン病の分子病態: α-synucleinとLRRK2をめぐって2007

    • Author(s)
      Iwatsubo T
    • Organizer
      第13回北海道パーキンソン病研究会
    • Place of Presentation
      札幌
    • Year and Date
      2007-06-23
    • Related Report
      2007 Annual Research Report
  • [Presentation] Role of α-synuclein aggregation in Parkinson' s disease.2007

    • Author(s)
      Iwatsubo T
    • Organizer
      第5回パーキンソン病シンポジウム高松
    • Place of Presentation
      高松
    • Year and Date
      2007-04-12
    • Related Report
      2007 Annual Research Report

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Published: 2005-04-01   Modified: 2018-03-28  

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