TLS phosphorylation-dependent RNA metabolism in Familial ALS6

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K07074
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Hiroshima Bunkyo Women's University
• Principal Investigator: FUJII RITSUKO 広島文教女子大学, 人間科学部, 教授 (90342716)
• Project Period (FY): 2016-04-01 – 2019-03-31
• 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

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.

Free Research Field

神経分子生物学

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。