2001 Fiscal Year Final Research Report Summary
Molecular Mechanisms of Neuronal Death and Strategies for Neuroprotection
| Project/Area Number |
09280104
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas (A)
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| Allocation Type | Single-year Grants |
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| Research Institution | JUNTENDO UNIVERSITY |
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Principal Investigator |
MIZUNO Yoshikuni Juntendo University School of Medicine, Professor, 医学部, 教授 (30049043)
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| 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)
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| Project Period (FY) |
1997 – 2000
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| Keywords | Neurodegeneration / Huntington's disease / Spinocerebellar Ataxia / Triplet repeat / Parkinson's disease / Environmental factors / Neurotrophic factors / Neuroregeneration |
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| 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
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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
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