| Project/Area Number |
08407017
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | Niigata university |
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Principal Investigator |
TSUJI Shoji Niigata University, Brain Research Institute, Professor, 脳研究所, 教授 (70150612)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Hajime Niigata University, Brain Research Institute, Assistant, 脳研究所, 助手 (20251845)
TANAKA Keiko Niigata University, Medical Hospital, Assistant, 医学部・附属病院, 助手 (30217020)
INUZUKA Takashi Niigata University, Medical Hospital, Lecturer, 医学部・附属病院, 講師 (50184734)
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| Project Period (FY) |
1996 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥30,400,000 (Direct Cost: ¥30,400,000)
Fiscal Year 1997: ¥8,800,000 (Direct Cost: ¥8,800,000)
Fiscal Year 1996: ¥21,600,000 (Direct Cost: ¥21,600,000)
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| Keywords | CAG repeat disease / CAG repeat / dentatorubral-pallidoluysian atrophy / polyglutamine / apoptosis / transglutaminase / aggregate body / nuclear inclusion / トリプレットリピート / トランスジェニックマウス / 脊髄小脳変性症2型 |
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| Research Abstract |
Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by various combinations of cerebellar ataxia and accompanying neurological symptoms. In our previous study, we discovered that DRPLA is caused by unstable expansion of a CAG repeat of the DRPLA gene on chromosome 12p13.31. To develop therapeutic measures for dentatorubral-pallidoluysian atrophy (DRPLA), we have developed a culture system which allow densitive and quantitative analysis of the toxicity caused by the expanded polyglutamine stretches of the gene for DRPLA.We discovered that expression of truncated DRPLA protein with expanded polyglutamine stretches but not of those with wild-type polyglutamine stretches results in formation of perinuclear as well as intranuclear aggregate formation. It was also found that the cells with the aggregate bodies frequently under go apoptotic cell death as measured by TUNEL assay. The results indicate that pocessing of mutant DRPLA protein is important to generate "toxic fragments" which have a potential for aggregate formation. Formation of nuclear inclusions was also confirmed in the neurons of cerebellar dentate nucleus of autopsied brains of patients with DRPLA, which confirms the role of intranuclear aggregate formation in the molecular mechanisms of neuronal degeneration in DRPLA.To further investigate the molecular mechanisms of aggregate formation, we tested various transglutaminase inhibitors. We found that cystamine and monodansylcadaverine significantly suppressed the aggregate formation and apoptotic cell death. The results raise the possibility that transglutaminase reaction is involved in the aggregate formation. Taken together, we have demonstrated a new strategy for the development of therapeutic measures for DRPLA.
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