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Mechanisms of neurodegeneration with NACP/α-synuclein, a causal gene of Parkinson's disease

Research Project

Project/Area Number 11680774
Research Category

Grant-in-Aid for Scientific Research (C)

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)

Project Period (FY) 1999 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2001: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2000: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1999: ¥900,000 (Direct Cost: ¥900,000)
KeywordsNACP / synuclein / Alzheimer / Parkinson / MSA / Lewy bodies / Alzheimaer
Research Abstract

We have found a novel component of Aizheimer's disease (AD) amyloid, named NAG (non-Abeta component of AD 'amyloid) and cloned the cDNA encoding NAG precursor protein, NACP. NACP is now known as human aipha-synuclein. We have shown that aipha-synuclein is aberrantly expressed not only in synaptic regions, but also In dystrophic neurites in AD brains. Recently, missense mutations In the alpha-synuclein gene were found in familial Parkinson's disease (PD) pedigrees In an autosomal dominant fashion and were shown to segregate with the illness. We have shown that entire molecule of aipha-synuclein constitutes filamentous components of Lewy bodies, a neuropathologlcal hallmark of PD and of dementia with Lewy bodies (DLB), and cytopiasmic inclusions of multiple system atrophy (MSA). It has been shown that recombinant aipha-synuclein forms fibrils in vitro like Lewy bodies and that the fibril formation Is accelerated with those mutations.
Thus, aipha-synuclein is a common pathogenic molecule In these degenerative diseases, and it seems that the accumulation of abnormal structures of aipha-synuclein within neurons, axons, dendrites, and presynaptic regions interfere the function of neuron, I.e., neurotransmlssion, leading to Parkinsonism and dementia as symptoms, and eventually to neuronal cell death. We have shown that the NAG region of aipha-synuclein, which is shown to be important for fibrillogenesis, is hard to digest by some protelnases. We also have revealed that tubulin is an alpha-synuclein-binding protein and that tubulin seeds aipha-synuclein fibril formation. We have cloned the gene for human aipha-synuclein and revealed the genomic structure of this gene, and found that there are polymorphisms in the promoter region and in an exon of aipha-synuclein gene.

Report

(4 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • Research Products

    (30 results)

All Other

All Publications (30 results)

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

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hossain S et al.: "Limited proteolysis of NACP/alpha-synuclein."J.Alzheimers Dis.. 3. 577-584 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Xia Y et al.: "Characterization of the human alpha-synuclein gene : Genomic structure, transcription start site, promoter region and polymorphisms."J.Alzheimers Dis.. 3. 485-494 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ishimura H et al.: "Changes in presynaptic proteins, SNAP-25 and synaptophysin, in the hippocampal CA1 area in ischemic gerbils."Brain Res.. 903. 94-101 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Togo T et al.: "Glial involvement in the degeneration process of Lewy body-bearing neurons and the degradation process of Lewy bodies in brains of dementia with Lewy bodies."J.Neurol.Sci.. 184. 71-75 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Iseki E et al.: "Neuropathological study of the disturbance of the nigro-amygdaloid connections in brains from patients with dementia with Lewy bodies"J.Neurol.Sci.. 185. 129-134 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Alim MA et al.: "Tubutin seeds α-synuciein fibrit formation."J.Blot.Chem.. 277. 2112-2117 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hossain S et al.: "Limited proteotysis of NACP/ α-synucleln."J.Alzheimers Dis.. 3. 577-584 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Xia Y et al.: "Characterization of the human α-Synuctein gene: Genomic structure, transcription start site, promoter region and polymorphisms."J.Alzheimers Dis.. 3. 485-494 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] tshimaru H et al.: "Changes in presynaptic proteins, SNAP-25 and synaptophysin, in the hippocampaiCAl area in ischemic"Brain Res.. 903. 94-101 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Iseki E et al.: "A neuropathotogicat study of the disturbance of the nigro-amygdaloid connections in brains from patients with dementia with Lewy bodies."J.Neurol.Sci.. 185. 129-134 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Togo T et al.: "Gliat involvement in the degeneration process of Lewy body-bearing neurons and the degradation process of Lewy bodies in brains of dementia with Lewy bodies."J.Neurot.Sci.. 184. 71-75 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Iseki E et al.: "Accumulation of human α-synuctein in different cytoskeietons in Lewy bodies in brains of dementia with Lewy bodies."Neurosci.Lett.. 290. 41-44 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Arima K et al.: "NACP/α-synuclein and tau constitute two distinctive subsets of filaments in the same neuronal inclusions in brains from a family of parkinsortism and dementia with Lewy bodies: double-immunolabeting fluorescence and electron microscopic studies."Acta Neuropathol.. 100. 115-121 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ancotlo K et al.: "α-Synuclein and the Parkinson's disease-related mutant Ala53Thr-α-synuclein do not undergo proteasomat degradation In HEK293 and neuronal cells."Neurosci.Lett.. 285. 79-82 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Shoji M et al.: "Accumulation of NACP/α-synuctein in Lewy body disease and muttiple system atrophy."J.Neurot.Neurosurg.Psychiatry. 68. 605-608 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Iseki E et al.: "Degeneration process of Lewy bodies in the brains of patients with dementia with Lewy bodies using α-synuclein-immunohistochemistry."Neurosci.Lett.. 286. 69-73 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yang F et al.: "Plaque-associated α-synuclein (NACP) pathology in aged transgenic mice expressing amyloid"Brain Res.. 853. 381-383 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Marul W et al.: "Occurrence of human α-synuctein immunoreactive neurons with neurofibritiary tangle formation in the limbic areas of patients with Alzheimers disease."J.Neurot.Sci.. 174. 81-84 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Marul W et al.: "An Autopsied case of Down syndrome with Alzheimer pathology and α-Synuciein immunoreactivity."Neuropathol.. 19. 410-416 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Iseki at al.: "ditnicopathotogical multiplicity of dementia with Lewy bodies."Neuropathol.. 19. 386-394 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Arima K et al.: "Cellular co-localization of phosphorytated tau-and NACP/α-synuctein-epitopes in Lewy bodies in sporadic Parkinson's disease and in dementia with Lewy bodies."Brain Res.. 843. 53-61 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Alim MA et al.: "α-Synuclein and neurodegeneration."Dementia Japan. 17. 75-82 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yoshii M et al.: "NACP (α-Synucteln).: a common key molecule in both Atzheimers and Parkinson's diseases"JaJ.Geriatric Psychiatry. 11. 791-801 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] E.Iseki,W.Marui, et al.: "Accumulation of human α-synuclein in different cytoskeletons in Lewy bodies in brains of dementia with Lewy bodies."Neuroscience Letters. 290. 41-44 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] K.Arima,T.Misutani, et al: "NACP/α-synuclein and tau constitute two distinctive subsets of filaments in the same neuronal inclusions in brains from a family of parkinsonism and dementia with Lewy bodies : double-immunolabeling fluorescence and electron microscopic studies."Acta Neuropathologica. 100. 115-121 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] K.Ancolio, et al.: "α-Synuclein and the Parkinson's disease-related mutant Ala53Thr-α-synuclein do not undergo proteasomal degradation in HEK293 and neuronal cells."Neuroscience Letters. 285. 79-82 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] M.Shoji, et al.: "Accumulation of NACP/α-synuclein in Lewy body disease and multiple system atrophy."J.Neurology, Neurosurgery and Psychiatry. 68. 605-608 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] E.Iseki,W.Marui, et al.: "Degeneration process of Lewy bodies in the brains of patients with dementia with Lewy bodies using α-synuclein-immunohistochemistry."Neuroscience Letters. 286. 69-73 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] F.Yang,K.Ueda, et al.: "Plaque-associated α-synuclein (NACP) pathology in aged transgenic mice expressing amyloid precursor protein."Brain Research. 853. 381-383 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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