| Project/Area Number |
13680821
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | Tottori University |
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Principal Investigator |
KATO Shinsuke Tottori University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (60194817)
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| Co-Investigator(Kenkyū-buntansha) |
OHAMA Eisaku Tottori University, Faculty of Medicine, Professor, 医学部, 教授 (50018892)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2003: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2002: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2001: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | Familial amyotrophic lateral sclerosis / Superoxide dismutase 1(SOD1) / Granule-coated fibril / Aggregation toxicity / Maillard reaction / Cupper chaperone for SOD / Hepatocyte growth factor / Redox system / superoxide dismutase 1 / c-Met / ペルオキシレドキシン / グルタチオンペルオキシダーゼ / 孤発性筋萎縮性側索硬化症 / 神経栄養因子 / cMet / レビー小体様硝子様封入体 / 残存運動ニューロン / Superroxide dismutase 1 / Granule-coated fibrils / Transgenic mouse / Advanced glycation endproducts / Copper chaperone for superoxide dismutase / Aggregation toxicity / 運動ニューロン死 |
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| Research Abstract |
We have elucidated the aggregation mechanism of the mutant superoxide dismutase1 (SOD1) in patients with familial amyotrophic lateral sclerosis with SOD1 gene mutation and their animal models. This mutant SOD1 aggregation leads to their motor neuron death. Granule-coated fibrils are ultrastructural morphological hallmarks of this mutant SOD1 aggregation toxicity. Maillard reaction [advanced glycation endproduct (AGE) formation] contributes to the granule-coated fibril formation : the formation of the AGE-modified SOD1 (probably AGE-modified mutant SOD1) is one of the mechanisms responsible for the aggregation (i.e.,granule-coated fibril formation), which leads to the neuronal cell death. The increase of these granule-coated fibrils means intracellular inclusion formation. When the inclusions have been growing, co-aggregation or sequestration into the inclusions (i.e.,granule-coated fibrils themselves) has been observed for normal cytosolic constitutive proteins, copper chaperone for SOD (chaperone specifically carried copper to SOD1), hepatocyte growth factor (neurotrophic factor), and proxiredoxin/glutathione peroxidase directly regulating a redox system. These are also endogenous mechanisms that accelerate neuronal death.
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