Cell-autonomous and non-cell-autonomous mechanisms of neurodegeneration in ALS
| Project/Area Number |
25293020
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Partial Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Pharmacology in pharmacy
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| Research Institution | Keio University |
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Principal Investigator |
Misawa Hidemi 慶應義塾大学, 薬学部, 教授 (80219617)
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| Co-Investigator(Renkei-kenkyūsha) |
YAMANAKA Koji 名古屋大学, 環境医学研究所, 教授 (80446533)
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| Project Period (FY) |
2013-04-01 – 2016-03-31
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| Project Status |
Completed (Fiscal Year 2015)
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| Budget Amount *help |
¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000)
Fiscal Year 2015: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2014: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2013: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
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| Keywords | 運動ニューロン / 筋萎縮性側索硬化症 / 神経変性疾患 / アストロサイト / ミクログリア / オステオポンチン / 細胞外マトリクス / 選択的脆弱性 / 神経変性 / グリア |
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| Outline of Final Research Achievements |
Selective vulnerability in motor neuron (MN) subtypes is a fundamental aspect of amyotrophic lateral sclerosis (ALS). MNs are subdivided into three motor units; fast-fatigable (FF), fast fatigue-resistant (FR) and slow (S). In ALS, FF MNs are more vulnerable than FR and S MNs. We found that the extracellular matrix (ECM) protein osteopontin (OPN) is selectively expressed by FR and S MNs, whereas matrix metalloproteinase-9 (MMP-9) is expressed by FF MNs. OPN is accumulated as extracellular granules in ECM in ALS mouse models and a familial ALS case. In SOD1G93A mice, OPN/MMP-9 double positivity marks remodeled FR and S MNs destined to compensate for lost FF MNs before ultimately dying. Genetic ablation of OPN in SOD1G93A mice shows dichotomic effects; disease onset is delayed but disease progression is accelerated. OPN induced MMP-9 up-regulation via αvβ3 integrin. Our results demonstrate that OPN is involved in the second-wave neurodegeneration by up-regulating MMP-9 in ALS.
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Report
(4 results)
Research Products
(24 results)
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[Journal Article] Neuregulin 1 confers neuroprotection in SOD1-linked amyotrophic lateral sclerosis mice via restoration of C-boutons of spinal motor neurons.2016
Author(s)
Lasiene J, Komine O, Fujimori-Tonou N, Powers B, Endo F, Watanabe S, Shijie J, Ravits J, Horner P, Misawa H, Yamanaka K
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Journal Title
Acta Neuropathologica Communications
Volume: 4
Issue: 1
Pages: 15-15
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] SIRT1 overexpression ameliorates a mouse model of SOD1-linked amyotrophic lateral sclerosis via HSF1/HSP70i chaperone system.2014
Author(s)
Watanabe S, Ageta-Ishihara N, Nagatsu S, Takao K, Komine O, Endo F, Miyakawa T, Misawa H, Takahashi R, Kinoshita M, Yamanaka K.
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Journal Title
Mol Brain
Volume: 7
Issue: 1
Pages: 62-62
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Selective disruption of acetylcholine synthesis in subsets of motor neurons: A new model of late-onset motor neuron disease.2014
Author(s)
Lecomte, M-J., Bertolus, C., Santamaria, J., Bauchet, A-L., Herbin, M., Saurini, F., Misawa, H., Maisonobe, T., Pradat, P-F. Nosten-Bertrand, M., Mallet, J. and Berrard S.
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Journal Title
Neurobiology of Disease
Volume: 65
Pages: 102-111
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Effect of secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1) on airway epithelial cells.2013
Author(s)
Narumoto O, Niikura Y, Ishii S, Morihara H, Okashiro S, Nakahari T, Nakano T, Matsumura H, Shimamoto C, Moriwaki Y, Misawa H, Yamashita N, Nagase T, Kawashima K, Yamashita N.
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Journal Title
Biochem Biophys Res Commun
Volume: 438
Issue: 1
Pages: 175-179
DOI
Related Report
Peer Reviewed
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