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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)
永津 俊治  藤田保健衛生大学, 医学部, 教授 (40064802)
Project Period (FY) 1997 – 2000
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥79,100,000 (Direct Cost: ¥79,100,000)
Fiscal Year 2001: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2000: ¥23,000,000 (Direct Cost: ¥23,000,000)
Fiscal Year 1999: ¥15,800,000 (Direct Cost: ¥15,800,000)
Fiscal Year 1998: ¥17,500,000 (Direct Cost: ¥17,500,000)
Fiscal Year 1997: ¥19,800,000 (Direct Cost: ¥19,800,000)
KeywordsNeurodegeneration / Huntington's disease / Spinocerebellar Ataxia / Triplet repeat / Parkinson's disease / Environmental factors / Neurotrophic factors / Neuroregeneration / 脊髄小脳変性病
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

Report

(6 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (37 results)

All Other

All Publications (37 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)

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

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [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)

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

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [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)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kubo S, et al.: "Parkin is associated with cellular vesicles"J Neruochem. 78. 42-54 (2001)

    • Related Report
      2001 Annual Research Report
  • [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)

    • Related Report
      2001 Annual Research Report
  • [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)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takanashi M, et al.: "ron accumulation in the substantia nigra of autosomal recessive juvenile parkinsonism (ARJP)"Parkinsonism Related Disord. 7. 311-314 (2001)

    • Related Report
      2001 Annual Research Report
  • [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)

    • Related Report
      2001 Annual Research Report
  • [Publications] Matsuyama N, et al.: "Identification and characterization of the miniature pig"Genomics. 69. 72-85 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yoshizawa T, et al.: "Cell cycle arrest enhances the in vitro cellular toxicity of the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch"Hum Mol Genet. 9. 69-78 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Shimura H, et al.: "Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase"Nature Genet. 25. 302-305 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kitada T, et al.: "Molecular cloning, gene expression, and identification of a splicing variant of the mouse parkin gene"Mammalian Genome. 11. 417-421 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tsuda M, et al.: "Selective solubilization of high-molecular-mass neurofilament subunit during nerve regeneration"J Neurochem. 74. 860-868 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ohsawa K, et al.: "Involvement of lba1 in membrane ruffling and phagocytosis of macrophages/microglia"Mammalian Genome. 113. 3073-3084 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Mizuno Y: "Genetics of Parkinson's disease"Biomed Pharmacother. 53. 109-116 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Shimura H: "Immunohistochemical and subcellular localization of Parkin protein: absence of protein in autosomal resessive Juyenile Parkinsonism patients"Ann Neurol. 45. 668-672 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Wang M,: "Polymorphism in the Parkin gene in sporadic Parkinson's disease"Ann Neurol. 45. 655-658 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hadano S: "A yeast artificia chromosome-based physical map of the juvenile amyottophic lateral sclerosis (ALS2) critical region on human chroimosome 2q33-34"Genomics. 55. 106-112 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kurachi M: "Real time obervation of the disassembly of stable neuritic microtubules induced by laser transection: possible mechanisms of microtubule stabilization in neurites"Genomics. 42. 87-99 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Shimojo M: "Neuroprotective action of a novel compound-M50463-in primary cultured neurons"Brain Res. 815. 131-139 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kitada T: "Deletion mutation in a novel protein “Parkin" gene causes autosomal recessive juvenile parkinsonism (AR-JP)" Nature. 39. 605-608 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Hattori N: "Point mutation (Thr240Arg and Gln311Stop) in the Parkin gene" Biochem Biophy Res Commun. 249. 754-758 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Matsumine H: "A microdeletion spanning D6S305 co-segregates with autosomal recessive juvenile parkinsonism (ARJP)" Genomics. 49. 143-146 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Hadano S: "The primary structure and genomic organaization of five novel transcripts located close to the Huntington's disease gene on human chromosome 4p16.3" DNA Research. 5. 177-186 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Chen Q: "Sequence of a 131-kb region of 5p13.1 containing the spinal muscular atrophy genes SMN and NAIP" Genomics. 48. 121-127 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ohbayashi K: "Stimulation of L-type Ca^<2+> channel in growth cones activates two independent signaling pathways" J Neurosci Res. 51. 682-696 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Matsumine H, Shimizu Y, Kobayashi T, Mizuno Y,et al.: "Paralysis agitans of early onset with marked diurnal fluctuation of symptoms (PEDF) maps to the locus for autosomal recessive juvenile parkinsonism (ARJP)" Neurology. (in press). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Matsumine H, Saito M, Shimoda-Matsubayashi S, Mizuno Y,et al.: "Localization of a gene for an autosomal recessive form juvenile parkinsonism to chromosome 6q25.2-27" Am J Hum Genet. 60. 588-596 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kogi M, Fukushige S, Lefevre,et al.: "A novel tamdem repeat sequence location on human chromosome 4p : lsolation and charactorization" Genomics. 42. 278-283 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Xu DG, Crocker SJ, Doucet,et al.: "Elavation of neuronal expression of NAIP reduces ischemic damage in the rat hippocampus" Nature Medicine. 3. 997-1004 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tashiro T, Komiya Y, Kurachi M, Kikumoto M, Tashiro H: "Direct visualization and characterization of stable microtubules from the neurites of cultured dorsal root ganglion cells" J Neurosci Res. 50. 81-93 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tsuda M, Tashiro T, Komiya Y: "lncreased solubility of high-molecular-mass neurofilament subunit by suppression of daphosphorylation : its relation to axonal ntransport" J Neurochem. 68. 2558-2565 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Mizuno Y, Ikebe S, Hattori N, Mochizuki H, Hattori Y, Kondo T: "Movement Disorders.Neurologic principles and practice (Etiology of Parkinson's disease )" Watts RL,Koller WC,eds,The McGraw-Hill,New York, 161-182(21) (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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