Grant-in-Aid for Scientific Research on Priority Areas (A).
|Research Institution||JUNTENDO UNIVERSITY|
MIZUNO Yoshikuni Juntendo University School of Medicine, Professor, 医学部, 教授 (30049043)
KOHSAKA Shinichi National Institute of Neuroscience, NCNP, Japan(NIN), Heads, 神経研究所, 部長 (50112686)
KANAZAWA Ichiro University of Tokyo, Professor, 医学部, 教授 (30110498)
永津 俊治 藤田保健衛生大学, 医学部, 教授 (40064802)
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)
|Project Fiscal Year
1997 – 2000
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)
|Keywords||Neurodegeneration / Huntington's disease / Spinocerebellar Ataxia / Triplet repeat / Parkinson's disease / Environmental factors / Neurotrophic factors / Neuroregeneration / 神経細胞死 / ハンチントン病 / 脊髄小脳変性症 / トリプレットリピート / パーキンソン病 / 環境因子 / 神経栄養因子 / 神経再生 / 脊髄小脳変性病|
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
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