2013 Fiscal Year Final Research Report
Novel function of sigma-1 receptor and therapeutics strategy for neurodegenerative disorders
| Project/Area Number |
24659024
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Single-year Grants |
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| Research Field |
Biological pharmacy
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| Research Institution | Tohoku University |
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Principal Investigator |
FUKUNAGA KOHJI 東北大学, 薬学研究科(研究院), 教授 (90136721)
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| Co-Investigator(Kenkyū-buntansha) |
SHIODA Norifumi 東北大学, 大学院薬学研究科, 助教 (00374950)
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| Project Period (FY) |
2012-04-01 – 2014-03-31
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| Keywords | 筋萎縮性側索硬化症 / シグマー１受容体 / ミトコンドリア障害 / 小胞体ストレス / メチルピルビン酸 / ALS治療薬 |
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| Research Abstract |
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder caused by motor neuron dysfunction. Recently, a E102Q mutation in the chaperone protein sigma-1 receptor (R) was discovered in familial ALS patients. Here, we address mechanisms underlying neurodegeneration caused by this mutation using overexpression analysis in neuro2A cells. Sigma-1R(E102Q) overexpression promoted its dissociation from the endoplasmic reticulum (ER) membrane and its cytoplasmic aggregation, and in turn impaired mitochondrial ATP production. Under ER stress condition, sigma-1R(E102Q) overexpression aggravated mitochondrial damage, thereby causing apoptosis. The enhancement of ATP production by methyl pyruvate treatment rescued mitochondrial damage induced by sigma-1R(E102Q) overexpression. Taken together, phenotypes observed in sigma-1R(E102Q)-overexpressing cells suggest that ATP supplementation by methyl pyruvate is potential therapeutic strategy to treat ALS caused by sigma-1R mutations.
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