Novel pathological pathway of ALS/FTLD-U
| Project/Area Number |
23591254
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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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 |
ITO Daisuke 慶應義塾大学, 医学部, 講師 (80286450)
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| Project Period (FY) |
2011 – 2013
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| Project Status |
Completed (Fiscal Year 2013)
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| Budget Amount *help |
¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2011: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
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| Keywords | ubiquitin / optineurin / 筋萎縮性側策硬化症 / endosome / autophagy / 前頭側頭葉変性症 / TDP-43 / FUS / ubiquilin / RNA / Ataxin2 |
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| Research Abstract |
Ubiquilin (UBQLN) 2 localized in endosomal vesicles formed by the ALS-linked molecule optineurin (OPTN) and also co-localized with an initiator of the autophagic process, ULK1, after amino acid starvation. OPTN-vesicles were ubiquitin- and p62-immunopositive. An ALS-linked mutation (E478G) in OPTN abolished vesicle formation. ALS-linked mutations in UBQLN2 additively enhanced UBQLN2 aggregation and formation of inclusion bodies, resulting in mislocation from OPTN-vesicles. UBQLN2 was found to be a potent regulator of the levels of OPTN and the FTD-linked secretory factor progranulin, possibly via the endosomal system, and ALS-linked mutations disturbed these functional consequences. This study demonstrates that ALS-linked mutations in both OPTN and UBQLN2 interfere with the constitution of specific endosomal vesicles, suggesting that the vesicles are involved in protein homeostasis and that these proteins function in common pathological processes.
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Report
(4 results)
Research Products
(31 results)
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[Journal Article] Establishment of induced pluripotent stem cells from centenarians for neurodegenerative disease research.2012
Author(s)
Yagi T, Kosakai A, Ito D*, Okada Y, Akamatsu W, Nihei Y, Nabetani A, Ishikawa F, Arai Y, Hirose N, Okano H, Suzuki N.
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Journal Title
Related Report
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[Journal Article] Stanninocalcin 2 is a negative modulator of store-operated calcium entry2011
Author(s)
Zeiger, W., Ito, D., Swetlik, C., Oh-hora, M., Villereal, ML. and Thinakaran, G.
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Journal Title
Mol Cell Biol
Volume: 31
Issue: 18
Pages: 3710-3722
DOI
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Peer Reviewed
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[Presentation] Generation of iPS cells from centenarians for neurodegenerative disease research.
Author(s)
八木拓也, 小堺有史, 伊東大介, 岡田洋平, 赤松和土, 二瓶義廣, 鍋谷彰, 石川冬木, 広瀬信義, 岡野栄之, 鈴木則.
Organizer
第31回日本認知症学会学術集会
Place of Presentation
茨城
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