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Identification of ALS linked FUS mutant induced pathological mechanism by genome-wide gene expression analyses

Research Project

Project/Area Number 15K07918
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Biological pharmacy
Research InstitutionHokkaido University

Principal Investigator

NAKAYA Tadashi  北海道大学, 薬学研究院, 助教 (50374559)

Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2015: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
KeywordsFUS / R495X / ALS / RNA-seq / CLIP-seq / Ribo-seq / 大規模シーケンス
Outline of Final Research Achievements

FUS has been identified as one of causative factors of Amyotrophic lateral sclerosis, however, its pathogenic mechanism is still unclear. To uncover it, I focused on R495X, a familial mutant of FUS, and tried to identify its targets using CLIP-seq and its effects on transcriptome and translatome by RNA-seq and Ribo-seq in genome-wide. I identified that R495X preferentially bound to mRNA in the cytoplasm by CLIP-seq. RNA-seq revealed that R495X had a moderate effect on RNA expression. By Ribo-seq, I found that R495X significantly altered the translation of genes related to mitochondria functions resulted in shortening of mitochondria and neurotoxicity. Importantly, a mutant of R495X, R495X4FL, which reduced an RNA binding ability, partially abrogated the phenotypes of R495X. These results indicate that R495X primarily impairs mitochondria by binding to mRNAs related to its functions. Moreover, my results highlight the importance of its RNA binding property of FUS on neurotoxicity.

Report

(4 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (4 results)

All 2017 2016 2015

All Presentation (4 results) (of which Int'l Joint Research: 1 results)

  • [Presentation] FUS regulates the expression of snRNP70 by binding to its conserved intron in neuron2017

    • Author(s)
      中矢 正
    • Organizer
      北米神経科学会SfN2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The relationship between cytotoxicity and function of FUS in neurons2016

    • Author(s)
      中矢 正
    • Organizer
      2015年度日本生化学会北海道支部・日本生物物理学会北海道支部合同シンポジウム
    • Place of Presentation
      北海道大学(北海道札幌市)
    • Year and Date
      2016-03-14
    • Related Report
      2015 Research-status Report
  • [Presentation] Identification of domains of FUS required for the regulation of genes with conserved introns.2015

    • Author(s)
      中矢 正
    • Organizer
      第58回日本神経化学会大会
    • Place of Presentation
      大宮ソニックシティ(埼玉県さいたま市)
    • Year and Date
      2015-09-11
    • Related Report
      2015 Research-status Report
  • [Presentation] In vivo における ALS 原因因子 FUS の標的 RNA の同定2015

    • Author(s)
      3.中矢 正、Panagiotis Alexiou, Manolis Maragkakis, Alexandra Chang, Zissimos Mourelatos
    • Organizer
      第17回日本RNA学会年会
    • Place of Presentation
      ホテルライフォート札幌(北海道札幌市)
    • Year and Date
      2015-07-15
    • Related Report
      2015 Research-status Report

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Published: 2015-04-16   Modified: 2019-03-29  

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