Atherapeutic approach to polyglutamine diseases by the activation of cellularproteolyticpathways
| Project/Area Number |
17300109
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Nerve anatomy/Neuropathology
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| Research Institution | Niigata University |
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Principal Investigator |
YAMADA Mitsunori Niigata University, Brain Research Ins, Associate Professor (30240039)
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| Co-Investigator(Kenkyū-buntansha) |
ONODERA Osamu Niigata University, Brain Research Ins, Associate Professor (20303167)
TAKAHASHI Hitoshi Niigata University, BrainResearch Ins, Professor (90206839)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥11,920,000 (Direct Cost: ¥10,900,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2007: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2006: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 2005: ¥5,100,000 (Direct Cost: ¥5,100,000)
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| Keywords | Polyglutamine disease / Pathology / Animal model / Protein analysis / Gene expression |
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| Research Abstract |
Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG repeat encoding a polyglutamine tract in the disease protein. In the studies of DRPLA, we have demonstrated that diffuse accumulation of mutant atrophi-1, DRPLA causative protein, in the neuronal nuclei, rather than the formation of neuronal intranuclear inclusions, was the predominant pathologic condition and involved a wide range of central nervous system regions far beyond the systems previously reported to be affected. The novel lesion distribution varies depending on the expanded sizes of CAG repeats, and may be responsible for a variety of clinical features, such as dementia and epilepsy in DRPLA. These pathologic conditions suggest that the degradation of accumulated mutant proteins may serve as a target for a new therapeutic approach to polyglutamine diseases. In the human DRPLA brains, we found that accumulated mutant atrophin-1 was decreased selectively in the hypertrophic neurons in the inferior olivary hypertrophy. Experimentally induced hypertrophy of the inferior olive in DRPLA mouse models also showed the decrease or disappearance of accumulated mutant proteins. Expression profile analyses demonstrated hypertrophy-dependent up- and down-regulations of genes. EttanTM DIGE (2-D Fluorescence Difference Gel Electrophoresis) analyses detected several molecules that were specifically induced in the hypertrophic olivary neurons.
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Report
(4 results)
Research Products
(33 results)
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[Journal Article] DRPLA.2007
Author(s)
山田光則
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Journal Title
Clinical Neuroscience 25
Pages: 850-851
Description
「研究成果報告書概要(和文)」より
Related Report
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[Journal Article] DRPLA2007
Author(s)
Yamada, M., et. al.
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Journal Title
Clin Neurosci 25
Pages: 850-851
Description
「研究成果報告書概要(欧文)」より
Related Report
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