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2001 Fiscal Year Final Research Report Summary

Molecular Mechanisms of Neuronal Death and Strategies for Neuroprotection

Research Project

Project/Area Number 09280104
Research Category

Grant-in-Aid for Scientific Research on Priority Areas (A)

Allocation TypeSingle-year Grants
Research InstitutionJUNTENDO UNIVERSITY

Principal Investigator

MIZUNO Yoshikuni  Juntendo University School of Medicine, Professor, 医学部, 教授 (30049043)

Co-Investigator(Kenkyū-buntansha) KANAZAWA Ichiro  University of Tokyo, Professor, 医学部, 教授 (30110498)
KOMIYA Yoshiaki  Gunma University School of Medicine, Professor, 医学部, 教授 (50010046)
IKEDA Joei  Tokai University Medical Research Institute, Professor, 総合医学研究所, 教授 (50266467)
KOHSAKA Shinichi  National Institute of Neuroscience, NCNP, Japan(NIN), Heads, 神経研究所, 部長 (50112686)
Project Period (FY) 1997 – 2000
KeywordsNeurodegeneration / Huntington's disease / Spinocerebellar Ataxia / Triplet repeat / Parkinson's disease / Environmental factors / Neurotrophic factors / Neuroregeneration
Research Abstract

We investigated molecular mechanisms of neuronal death in hereditary neurologic disorders due to CAG-triplet repeat diseases such as Huntington's disease and spinocerebellar ataxias. Also we investigated molecular mechanisms of nigral neuronal death in Parkinson's disease, which is a representative neurodegenerative disorders caused by the interaction of environmental factors and genetic predisposition. In addition, we investigated strategies for protecting these neurons from degeneration.
Regarding CAG-triplet repeat disorders, we succeeded in the generation of transgenic animals of Huntington's disease, dentatorubral-pallidoluysian degeneration, and Machado-Joseph disease. We found translocation of mutated atrophin-3 protein including the elongated polyglutamine stretch to the nucleus. Translocated mutant proteins formed intranuclear inclusions. In addition, mutated atrophin-3 interacted with a transfer factor and inhibited CREB-dependent activation of transcription.
In Parkinson's dis … More ease, we identified the gene for an autosomal recessive form of familial Parkinson's disease linked to the long arm of chromosome 6 and named it as parkin. Then we analyzed the function of the parkin protein and found that the parkin protein was an ubiquitin-protein ligase. Furthermore, we identified candidate substrates for the parkin protein, including 22 kDa alpha-synuclein and PAEL (Parkin-interacting endothelin receptor like) receptor. Accumulation of these proteins was also confirmed in patients with parkin mutations. Thus accumulation of such substrates may be responsible for neurodegeneration of the substantia nigra. In sporadic Parkinson's disease, we identified candidate endogenous neurotoxins, I.e., N-methylRsalsolinol and 3'4'-dihydroxybenzyl tetrahydroisoquinoline, which may contribute to nigral neurodegeneration.
Then we investigated strategies for neuroprotection. We found that Bcl-2 interacted with Smn and augmented neuroprotective properties of Bcl-2. In addition, we found a new protein, DP5, which was activated when the apoptosis cascade was activated. Furthermore, we found a new neurotrophic factor derived from the liver. This substance stimulated significantly the regeneration of the peripheral as well as central neurons.
Thus our group elucidated many important molecular pathways, which lead neurons to death. We contributed greatly to the understanding of molecular mechanism of neurodegeneration and neuroprotection. Less

  • Research Products

    (6 results)

All Other

All Publications (6 results)

  • [Publications] Imai Y, , et al.: "An unfolded putative transmembrane polypeptide,which can lead to endoplasmic reticulum stress,is a substrate of parkin"Cell. 105. 891-902 (2001)

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      「研究成果報告書概要(和文)」より
  • [Publications] Kubo S, et al.: "Parkin is associated with cellular vesicles"J Neruochem. 78. 42-54 (2001)

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      「研究成果報告書概要(和文)」より
  • [Publications] Lu CS, et al.: "Clinical and genetic studies on familial parkinsonism: The first report on a parkin gene mutation in a Taiwanese family"Mov Disord. 253. 164-166 (2001)

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      「研究成果報告書概要(和文)」より
  • [Publications] Shimura H, et al.: "Ubiquitination of a new form of α-synuclein by parkin from human brain:Implications for Parkinson's disease"Science. 293. 263-269 (2001)

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      「研究成果報告書概要(和文)」より
  • [Publications] Takanashi M, et al.: "ron accumulation in the substantia nigra of autosomal recessive juvenile parkinsonism(ARJP)"Parkinsonism Related Disord. 7. 311-314 (2001)

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      「研究成果報告書概要(和文)」より
  • [Publications] Wang M, et al.: "Developmental changes in the expression of parkin and UbcR7,a parkin-interacting and ubiquitin-conjugating enzyme,in rato brain"J Neurochem. 77. 1561-1568 (2001)

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      「研究成果報告書概要(和文)」より

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Published: 2003-09-17  

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