Common defects of RNA metabolism in motor neuron diseases SMA and ALS
| 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 |
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| 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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Report
(5 results)
Research Products
(20 results)
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[Journal Article] Establishment of in vitro FUS-associated familial amyotrophic lateral sclerosis model using human induced pluripotent stem cells.2016
Author(s)
Naoki Ichiyanagi, Koki Fujimori, Masato Yano, Chikako Ishihara-Fujisaki, Takefumi Sone, Tetsuya Akiyama, Yohei Okada, Wado Akamatsu, Takuya Matsumoto, Mitsuru Ishikawa, Yoshinori Nishimoto, Yasuharu Ishihara, Tetsushi Sakuma, Takashi Yamamoto, Hitomi Tsuiji, Naoki Suzuki, Hitoshi Warita, Masashi Aoki, Hideyuki Okano
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Journal Title
Stem Cell Reports
Volume: 6
Issue: 4
Pages: 496-510
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] Spliceosome integrity is defective in motor neuron disease ALS and SMA2013
Author(s)
Tsuiji H., Iguchi Y., Furuya A., Kataoka A., Hatsuta H., Atsuta N., Tanaka F.Hashizume Y., Akatsu H., Murayama S., Sobue G., Yamanaka K.
Organizer
第３６回日本神経科学大会
Place of Presentation
京都国際会議場
Related Report
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