| Project/Area Number |
16K07074
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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 |
Neurochemistry/Neuropharmacology
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| Research Institution | Hiroshima Bunkyo Women's University |
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Principal Investigator |
FUJII RITSUKO 広島文教女子大学, 人間科学部, 教授 (90342716)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | ＡＬＳタイプ６ / ＲＮＡ代謝 / ＴＬＳ／ＦＵＳ / エクソソーム / リン酸化シグナル / ALSタイプ６ / RNA代謝 / TLS/FUS / FUS/TLS / RNA輸送 / 脳神経疾患 / 神経科学 / シグナル伝達 |
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| Outline of Final Research Achievements |
A multi-functional RNA binding protein TLS/FUS has been identified as a cause of familial ALS type6 and potentially tends to form the intracellular protein-RNA aggregates which eventually develop the neuronal degeneration. In this study, we found that a novel tyrosine phosphorylation of TLS/FUS by the Src family kinase activity was required for the assembly of TLS-RNA exosomes and their subsequent release upon the prolonged depolarization of the spinal motor neurons. This Src-dependent tyrosine phosphorylation was accompanied by the asymmetric arginine-dimethylation of TLS/FUS at R216 and R218 by PRMT1/8 which has recently been shown to promote the nuclear-transport of TLS/FUS. Our findings indicate that the specific tyrosine phosphorylation of TLS/FUS, as well as its asymmetric arginine-dimethylation, plays a pivotal role in RNA metabolism to improve the cytotoxic TLS/FUS aggeregate-formation in the spinal motor neurons.
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| Academic Significance and Societal Importance of the Research Achievements |
非対称ジメチルアルギニン化TLSは細胞内凝集沈殿を抑制する他、将来的にはALS6の発症初期に形成されるTLS-RNA凝集体のマーカーとしても利用できる。また、TLS-RNA凝集体に含まれるRNAの塩基配列を得ることができれば、この凝集体を選択的に分解する治療薬となるRNAアプタマーの設計が可能となるだろう。今後、本研究で得られた知見をALS6の治療や早期発見につなげるためには、RNAエクソソームとして細胞外放出されるRNAの実体とその機能の詳細な解析が待たれる。
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