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Molecular pathophysiology of α-Synuclein : Molecular mechanisms of neurodegenerative diseases

Research Project

Project/Area Number 14380363
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurochemistry/Neuropharmacology
Research InstitutionTokyo Metropolitan Organization for Medical Research

Principal Investigator

UEDA Kenji  Tokyo Metropolitan Organization for Medical Research, Tokyo Institute of Psychiatry, Senior Research Scientist, 東京都精神医学総合研究所, 主任研究員 (90261180)

Co-Investigator(Kenkyū-buntansha) YOSHII Mitsunobu  Tokyo Metropolitan Organization for Medical Research, Tokyo Institute of Psychiatry, Senior Principal Research Scientist, 東京都精神医学総合研究所, 参事研究員 (60091047)
AIZAWA Takako  Tokyo Metropolitan Organization for Medical Research, Tokyo Institute of Psychiatry, Technical Research Scientist, 東京都精神医学総合研究所, 研究員 (40415542)
HISANAGA Shinichi  Tokyo Metropolitan University, Faculty of Urban Liberal Arts, Professor, 都市教養学部, 教授 (20181092)
Project Period (FY) 2002 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥14,900,000 (Direct Cost: ¥14,900,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 2004: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2003: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 2002: ¥5,500,000 (Direct Cost: ¥5,500,000)
KeywordsNAC / NACP / Lewy bodies / Parkinson / Alzheimer / MAP / Tubulin / Gene regulation / Synuclein / 神経変性 / 細胞毒性
Research Abstract

After biochemical investigations of SDS-insoluble materials from Alzheimer's disease (AD) brains, two unknown peptides were identified and named as non-Aβ component of AD amyloid (NAC), and the precursor protein of NAC, NACP was identified by cDNA cloning (Ueda et al. 1993). NACP is now known as human α-Synuclein (aS). Since in both AD and Parkinson's disease (PD) brains neurodegeneration occurs in those areas where aS is highly expressed, it is possible that the amount of aS is the key factor for the degeneration. In AD we have shown an altered expression of aS in abnormal synaptic terminals and dystrophic neurites. In PD and dementia with Lewy bodies (LBs), we have shown that the main filamentous component of LBs is aS, as well as with the case of main filamentous component of neuronal and glial cytoplasmic inclusions of multiple system atrophy (MSA). To understand the pathophysiological role of aS, we have performed affinity chromatography using aS column and human brain proteins and revealed tubulin to be an aS binding protein. aS induced polymerization of purified tubulin into microtubules. This activity was as high as that of tau. Mutant forms of aS lost this potential. Now we can see a striking resemblance between aS and tau : both have the same physiological function and pathological features, making abnormal structures in diseased brains known as Synucleinopathies and Tauopathies. This paper (Alim et al. JAD 2004) was press released for public as "Breaking News" from the Web site of the American Association of the Advancement of Science (AAAS) in 2004. In aS-transfected dopaminergic MES23.5 cells, we have shown the inhibition of tyrosine hydroxylase (TH) expression, suggesting a role of aS in the regulation of the TH gene. TH is a rate-limiting enzyme for the synthesis of dopamine. Also in MES23.5 cells, we have shown that oxidative stress induces nuclear translocation of the C-terminus of endogenous aS, implying a role of aS in the nucleus.

Report

(5 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (40 results)

All 2006 2005 2004 2003 2002 Other

All Journal Article (22 results) Book (4 results) Publications (14 results)

  • [Journal Article] Oxidative stress induces nuclear translocation of C-terminus of α-synuclein in dopaminergic cells2006

    • Author(s)
      Xu S.et al.
    • Journal Title

      Biochemical and Biophysical Research Communications 342

      Pages: 330-335

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Oxidative stress induces nuclear translocation of C-terminus of alpha-synuclein in dopaminergic cells.2006

    • Author(s)
      Xu S et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 342

      Pages: 330-335

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Oxidative stress induces nuclear translocation of C-terminus of α-synuclein in dopaminergic dells.2006

    • Author(s)
      Xu S.et al.
    • Journal Title

      Biochemical and Biophysical Research Communication 342

      Pages: 330-335

    • Related Report
      2005 Annual Research Report
  • [Journal Article] α-Synuclein and Dopamine Metabolism.2005

    • Author(s)
      Yu S.et al.
    • Journal Title

      Molecular Neurobiology 31

      Pages: 243-254

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] α-Synuclein and Dopamine Metabolism.2005

    • Author(s)
      Yu S.et al.
    • Journal Title

      Mol.Neurobiol. (In press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Demonstration of a role for alpha-synuclein as a functional microtubule-associated protein.2004

    • Author(s)
      Alim MA et al.
    • Journal Title

      J.Alzheimer's Dis. 6

      Pages: 435-442

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Inhibition of tyrosine hydroxylase expression in alpha-synuclein-transfected dopaminergic neuronal cells.2004

    • Author(s)
      Yu S et al.
    • Journal Title

      Neurosci.Left. 367

      Pages: 34-39

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Increased expression of neuronal cyclooxygenase-2 in the hippocampus in amyotrophic lateral sclerosis both with and without dementia.2004

    • Author(s)
      Yokota O et al.
    • Journal Title

      Acta Neuropathol. 107

      Pages: 399-405

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] NACP/alpha-synuclein immunoreactivity in diffuse neurofibrillary tangles with calcification (DNTC).2004

    • Author(s)
      Yokota O et al.
    • Journal Title

      Acta Neuropathol. 104

      Pages: 333-341

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Demonstration of a role for alpha-synuclein as a functional microtubleassociated protein.2004

    • Author(s)
      Alim M.A.et al.
    • Journal Title

      J.Alzheimers.Dis. 6

      Pages: 435-442

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Inhibition of tyrosine hydroxylase expression in alpha-synuclein-transfected dopaminergic neuronal cells.2004

    • Author(s)
      Yu S.et al.
    • Journal Title

      Neurosci.Lett. 367

      Pages: 34-39

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Increased expression of neuronal cyclooxygenase-2 in the hippocampus in amyotrophic lateral sclerosis both with and without dementia.2004

    • Author(s)
      Yokota O.et al.
    • Journal Title

      Acta Neuropathol. 107

      Pages: 339-405

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Microtubule dynamics can be central in Parkinson's disease as well as in Alzheimer's disease.2004

    • Author(s)
      Yoshii M., Ueda K.
    • Journal Title

      Psychogeriatrics 4(In press)

    • NAID

      10018089229

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Variability and heterogeneity in Alzheimer's disease with cotton wool plaques: a clinicopathological study of four autopsy cases.2003

    • Author(s)
      Yokota O et al.
    • Journal Title

      Acta Neuropathol. 106

      Pages: 348-356

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Glial involvement in diffuse Lewy body disease.2003

    • Author(s)
      Terada S et al.
    • Journal Title

      Acta Neuropathol. 105

      Pages: 163-169

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Motor dysfunction and gliosis with preserved dopaminergic markers in human alpha-synuclein A30P transgenic mice.2003

    • Author(s)
      Gomez-Isla T et al.
    • Journal Title

      Neurobiol.Aging 24

      Pages: 245-258

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Dementia with Lewy bodies showing advanced Lewy pathology but minimal Alzheimer pathology --Lewy pathology causes neuronal loss inducing progressive dementia.2002

    • Author(s)
      Uchikado H et al.
    • Journal Title

      Clin.Neuropathol. 21

      Pages: 269-277

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Torsin A and heat shock proteins act as molecular chaperones : suppression of alpha-synuclein aggregation.2002

    • Author(s)
      McLean PJ et al.
    • Journal Title

      J.Neurochem. 83

      Pages: 846-854

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Alpha-Synuclein, NAC, and beta-amyloid pathology of familial Alzheimer's disease cases bearing the E184D presenilin-1 mutation : a clinicopathological study.2002

    • Author(s)
      Yokota O et al.
    • Journal Title

      Acta Neuropathol. 104

      Pages: 637-648

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Immunohistochemical study of synphilin-1 in brains of patients with dementia with Lewy bodies - synphilin-1 is non-specifically implicated in the formation of different neuronal cytoskeletal inclusions.2002

    • Author(s)
      Iseki E et al.
    • Journal Title

      Neurosci.Left. 326

      Pages: 211-215

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Progression and staging of Lewy pathology in brains from patients with dementia with Lewy bodies.2002

    • Author(s)
      Marui Wet al.
    • Journal Title

      J.Neurol.Sci. 195

      Pages: 153-159

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Relationship in the formation process between neurofibrillary tangles and Lewy bodies in the hippocampus of dementia with Lewy bodies brains.2002

    • Author(s)
      Iseki E et al.
    • Journal Title

      J.Neurol.Sci. 195

      Pages: 85-91

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] 老年期認知症ナビゲータ2006

    • Author(s)
      平井俊策編, 上田健治分担執筆
    • Publisher
      メディカルレビュー社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] Cell Biology Protocols2006

    • Author(s)
      Rickwood D ed., K. Ueda分担執筆
    • Publisher
      John Wiley & Son, Ltd
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] 老年期認知症ナビゲータ2006

    • Author(s)
      平井俊策編(上田健治分担執筆)
    • Publisher
      メディカルレビュー社(印刷中)
    • Related Report
      2005 Annual Research Report
  • [Book] Cell Biology Protocols2006

    • Author(s)
      Harris G.et al.ed.(K.Ueda分担執筆)
    • Publisher
      John Wiley & Sons, Ltd(印刷中)
    • Related Report
      2005 Annual Research Report
  • [Publications] Uchikado H et al.: "Dementia with Lewy bodies showing advanced Lewy pathology but minimal Alzheimer pathology - Lewy pathology causes neuronal loss inducing progressive dementia."Clin.Neuropathol.. 21. 269-277 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Gomez-Isla T et al.: "Motor dysfunction and gliosis with preserved dopaminergic markers in human alpha-synuclein A30P transgenic mice."Neurobiol.Aging. 24. 245-258 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Terada S et al.: "Glial involvement in diffuse Lewy body disease."Acta Neuropathol.. 105. 163-169 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yokota O et al.: "Variability and heterogeneity in Alzheimer's disease with cotton wool plaques : a clinicopathological study of four autopsy cases."Acta Neuropathol.. 106. 348-356 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 上田健治: "Synucleinの分子病理:最近のトピック"精神医学. 45(8). 857-862 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ma QL et al.: "Alpha-Synuclein aggregation and neurodegenerative diseases."J.Alzheimers Dis.. 5. 139-148 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 馬 秋蘭ら: "アルツハイマー病の病因論の進展"診断と治療. 91(2). 321-332 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Alim MA et al.: "Tubulin seeds alpha-synuclein fibril formation"J. Biol. Chem.. 277. 2112-2117 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Iseki E et al.: "Relationship in the formation process between neurofibrillary tangles and Lewy bodies in the hippocampus of dementia with Lewy bodies brains"J. Neurol. Sci.. 195. 85-91 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Marui W et al.: "Progression and staging of Lewy pathology in brains from patients with dementia with Lewy bodies"J. Neurol. Sci.. 195. 153-159 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Iseki E et al.: "Immunohistochemical study of synphilin-1 in brains of patients with dementia with Lewy bodies -synphilin-1 is non-specifically implicated in the formation of different neuronal cytoskeletal inclusions"Neurosci. Lett.. 326. 211-215 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yokota O et al.: "NACP/alpha-synuclein immunoreactivity in diffuse neurofibrillary tangles with calcification (DNTC)"Acta Neuropathol.. 104. 333-341 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yokota O et al.: "Alpha-Synuclein, NAC, and beta-amyloid pathology of familial Alzheimer's disease cases bearing the E184D presenilin-1 mutation : a clinicopathological study"Acta Neuropathol.. 104. 637-648 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] McLean PJ et al.: "Torsin A and heat shock proteins act as molecular chaperones : suppression of alpha-synuclein aggregation"J. Neurochem.. 83. 846-854 (2002)

    • Related Report
      2002 Annual Research Report

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

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