Elucidation of mechanisms for neuronal death caused by mutant genes in amyotrophic lateral sclerosis
| Project/Area Number |
15590908
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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 |
Neurology
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| Research Institution | Keio University |
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Principal Investigator |
NIIKURA Takako Keio University, Department of Medicine, Instructor, 医学部, 助手 (10301491)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Keywords | neurodegenerative disease / amyotrophic lateral sclerosis / neuronal death / superoxide dismutase / ALS2 / alsin / スーパーオキシドジスムターゼ / Alsin |
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| Research Abstract |
Amyotrophic lateral sclerosis(ALS) is a progressive fatal neurodegenerative disease that is characterized with specific degeneration of motor neurons. Specific mutations in superoxide dismutase 1(SOD1) are associated with approximately 20% of familial ALS(FALS) cases. SOD1 mutants are considered to cause motoneuronal death by ‘gain of toxic function'. On the other hand, alsin encoded by another FALS-responsible gene, ALS2, is considered to cause ALS by ‘loss of function', because FALS-linked mutations in ALS2 are recessively inherited. Based on the hypothesis that alsin contributes neuroprotection, we examined whether wild-type alsin protect cells from SOD1 mutants-induced toxicity. We found that co-expression of alsin with FALS-linked SOD1 mutant drastically suppressed SOD1 mutants-induced cell death in motoneuronal cell line. Further, the wild-type alsin binds to FALS- linked SOD1 mutants, but not to wild-type SOD1, suggesting that neuroproptection of alsin correlates with complex formation with SOD1 mutants.
We also found that ADNF, a nine-residue polypeptide, suppressed motoneuronal death caused by FALS-linked SOD1 mutants in vitro and improved motor performance of G93A-SOD1 transgenic mice, a model of FALS.
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Report
(3 results)
Research Products
(40 results)
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[Journal Article] A Humanin derivative, S14G-HN, prevents amyloid-β-induced memory impairment in mice.2005
Author(s)
Tajima H, Kawasumi M, Chiba T, Yamada M, Yamashita K, Nawa M, Kita Y, Kouyama K, Aiso S, Matsuoka M, Niikura T, Nishimoto I.
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Journal Title
J.Neurosci.Res. 79(5)
Pages: 714-723
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Neuroprotective effect of activity-dependent neurotrophic factor, ADNF, against toxicity by familial amyotrophic lateral sclerosis-linked mutant SOD1 in vitro and in vivo.2005
Author(s)
Chiba T, Hashimoto Y, Tajima H, Yamada M, Kato R, Niikura T, Terashita K, Schulman H, Aiso S, Kita Y, Matsuoka M, Nishimoto I.
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Journal Title
J.Neurosci.Res. 78(4)
Pages: 542-552
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Molecular characterization of neuronal cell death by Alzheimer's amyloid-b peptides via D75NTR/PLAIDD.2004
Author(s)
Hashimoto Y, Kaneko Y, Tsukamoto E, Frankowski H, Kouyama K, Kita Y, Niikura T, Aiso S, Bredesen DE, Matsuoka M, Nishimoto I.
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Journal Title
J.Neurochem. 90(3)
Pages: 549-558
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Humanin antagonists : mutants that interfere with dimerization inhibit neuroproteiction by Humanin.2004
Author(s)
Hashimoto Y, Terashita K, Niikura T, Yamagishi Y, Ishizaka M, Kanekura K, Chiba T, Yamada M, Kita Y, Aiso S, Matsuoka M#, Nishimoto I.
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Journal Title
Eur.J.Neurosci. 19(9)
Pages: 2356-2364
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Analysis of neurons created from wild-type and Alzheimer's mutation knock-in embryonic stem cells by a highly efficient differentiation protocol.2004
Author(s)
Abe Y, Kouyama K, Tomita T, Tomita Y, Ban N, Nawa M, Matsuoka M, Niikura T, Aiso S, Kita Y, Iwatsubo T, Nishimoto I.
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Journal Title
J.Nuerosci. 23(24)
Pages: 8513-8525
Description
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[Journal Article] Implanted cannula-mediated repetitive administration of Aβ25-35 into the mouse cerebral ventricle effectively impairs spatial working memory.
Author(s)
Yamada M, Chiba T, Sasabe J, Nawa M, Tajima H, Niikura T, Terashita K, Aiso S, Kita Y, Matsuoka M, Nishimoto I.
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Journal Title
Behavioral Brain Research (in press)
Description
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