| Project/Area Number |
25430055
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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 |
Nerve anatomy/Neuropathology
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| Research Institution | Nagoya City University (2014-2016)
Institute of Physical and Chemical Research (2013) |
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Principal Investigator |
Tsuiji Hitomi 名古屋市立大学, 大学院薬学研究科, 講師 (40455358)
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| Co-Investigator(Kenkyū-buntansha) |
内匠 透 国立研究開発法人理化学研究所, 脳科学総合研究センター, チームリーダー (00222092)
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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 – 2017-03-31
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| Project Status |
Completed (Fiscal Year 2016)
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| Budget Amount *help |
¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
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| Keywords | 運動ニューロン / ALS / SMA / スプライソソーム / TDP-43 / FUS / SMN / スプライシング / 筋萎縮性側索硬化症 / 脊髄性筋萎縮症 / RNA代謝異常 / RNA代謝 |
|---|
| Outline of Final Research Achievements |
Two motor neuron diseases, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are caused by distinct genes involved in RNA metabolism, TDP-43 and FUS, and SMN, respectively. However, whether there is a shared defective mechanism in RNA metabolism common to these two diseases remains unclear. Here, we show that TDP-43 and FUS localize in nuclear Gems through an association with SMN, and that all three proteins function in spliceosome maintenance. We also show that in ALS, Gems are lost, U snRNA levels are up-regulated and spliceosomal U snRNPs abnormally and extensively accumulate in motor neuron nuclei. This aberrant accumulation of U snRNAs in ALS motor neurons indicates both ALS and SMA motor neurons have defects in the spliceosome. These findings indicate that a profound loss of spliceosome integrity is a critical mechanism common to neurodegeneration in ALS and SMA, and may explain cell-type specific vulnerability of motor neurons.
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