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A common interactor of protein aggregates associated with ALS/FTD and polyglutamine diseases

Research Project

Project/Area Number 16K09683
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Neurology
Research InstitutionMeiji Pharmaceutical University

Principal Investigator

Kino Yoshihiro  明治薬科大学, 薬学部, 准教授 (80415140)

Project Period (FY) 2016-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsポリグルタミン / ALS / FTD / C9orf72 / 凝集 / MLF2 / リピート伸長 / ポリグルタミン病 / 核内凝集体 / ALS/FTD / リピート伸長疾患 / RNA結合タンパク質 / ALS / タンパク質凝集 / 神経変性疾患 / FTD
Outline of Final Research Achievements

GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is a major genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat expansion of C9orf72 leads to the production of dipeptide repeats from the expanded RNA. Here, we searched for proteins that co-aggregate with Gly-Ala (GA) dipeptide repeat as well as polyglutamine (polyQ) in order to identify common interactors of different types of protein aggregates. We screened proteins that colocalized with aggregates of GA repeat and polyQ in Neuro2a cells and found Mlf2 as a common interactor. We found the binding proteins of Mlf2, including some cytoskeletal or nuclear proteins. In the brain, endogenous Mlf2 was localized in the nucleus and the neurites in wild-type mice. However, in a polyQ disease model mice, Mlf2 was observed in the aggregates and its distribution in the neurites was weakened. Thus, it is likely that the function of Mlf2 may be compromised by the pathogenic repeat proteins.

Academic Significance and Societal Importance of the Research Achievements

神経難病と呼ばれる疾患は数多く存在し、治療法が確立されていないものも多い。そのような疾患の一つ、筋萎縮性側索硬化症(ALS)は発症後わずか数年で寝たきりになり、治療薬も限られている。C9orf72遺伝子に存在するGGGGCCリピート配列の異常伸長はALSで最も頻度の高い変異であり、そこから異常なリピートタンパク質が発現する。同様の疾患として、CAGリピート配列の伸長によるポリグルタミン病が以前から知られている。本課題では両疾患群に共通して関わるタンパク質を探索し、複数の神経疾患に関わる重要因子の特定を目指した。そのような因子の候補としてMLF2を見出し、その性状について明らかにした。

Report

(5 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (20 results)

All 2019 2018 2017 2016

All Journal Article (11 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 11 results,  Open Access: 10 results,  Acknowledgement Compliant: 1 results) Presentation (8 results) (of which Int'l Joint Research: 1 results,  Invited: 2 results) Book (1 results)

  • [Journal Article] Microglia express GPNMB in the brains of Alzheimer's disease and Nasu-Hakola disease2019

    • Author(s)
      Satoh Jun-ichi、Kino Yoshihiro、Yanaizu Motoaki、Ishida Tsuyoshi、Saito Yuko
    • Journal Title

      Intractable & Rare Diseases Research

      Volume: 8 Issue: 2 Pages: 120-128

    • DOI

      10.5582/irdr.2019.01049

    • NAID

      130007663178

    • ISSN
      2186-361X, 2186-3644
    • Year and Date
      2019-05-31
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Microglia express TMEM119 in the brains of Nasu-Hakola disease2019

    • Author(s)
      Satoh Jun-ichi、Kino Yoshihiro、Yanaizu Motoaki、Ishida Tsuyoshi、Saito Yuko
    • Journal Title

      Intractable & Rare Diseases Research

      Volume: 8 Issue: 4 Pages: 260-265

    • DOI

      10.5582/irdr.2019.01123

    • NAID

      130007784569

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease2019

    • Author(s)
      Sone Jun、Mitsuhashi Satomi et al.
    • Journal Title

      Nature Genetics

      Volume: 51 Issue: 8 Pages: 1215-1221

    • DOI

      10.1038/s41588-019-0459-y

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Meroterpenoids with BACE1 Inhibitory Activity from the Fruiting Body of Boletinus asiaticus2019

    • Author(s)
      Yatsu Genki、Kino Yoshihiro、Sasaki Hiroaki、Satoh Jun-ichi、Kinoshita Kaoru、Koyama Kiyotaka
    • Journal Title

      Journal of Natural Products

      Volume: 82 Issue: 7 Pages: 1797-1801

    • DOI

      10.1021/acs.jnatprod.8b01092

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Tandem-genotypes: robust detection of tandem repeat expansions from long DNA reads2019

    • Author(s)
      Satomi Mitsuhashi, Martin C. Frith, Takeshi Mizuguchi, Satoko Miyatake, Tomoko Toyota, Hiroaki Adachi, Yoko Oma, Yoshihiro Kino, Hiroaki Mitsuhashi, Naomichi Matsumoto
    • Journal Title

      Genome Biology

      Volume: 20 Issue: 1 Pages: 58-58

    • DOI

      10.1186/s13059-019-1667-6

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Microglia express gamma-interferon-inducible lysosomal thiol reductase in the brains of Alzheimer's disease and Nasu-Hakola disease2018

    • Author(s)
      Satoh Jun-ichi、Kino Yoshihiro、Yanaizu Motoaki、Ishida Tsuyoshi、Saito Yuko
    • Journal Title

      Intractable & Rare Diseases Research

      Volume: 7 Issue: 4 Pages: 251-257

    • DOI

      10.5582/irdr.2018.01119

    • NAID

      130007533903

    • ISSN
      2186-361X, 2186-3644
    • Year and Date
      2018-11-30
    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Small nuclear RNA-mediated modulation of splicing reveals a therapeutic strategy for a TREM2 mutation and its post-transcriptional regulation2018

    • Author(s)
      Yanaizu Motoaki、Sakai Kenji、Tosaki Youhei、Kino Yoshihiro、Satoh Jun-ichi
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 6937-6937

    • DOI

      10.1038/s41598-018-25204-2

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Alzheimer's disease pathology in Nasu-Hakola disease brains2018

    • Author(s)
      Satoh JI, Kino Y, Yanaizu M, Saito Y.
    • Journal Title

      Intractable & Rare Diseases Research

      Volume: 7 Issue: 1 Pages: 32-36

    • DOI

      10.5582/irdr.2017.01088

    • NAID

      130006507559

    • ISSN
      2186-361X, 2186-3644
    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Microglia express ABI3 in the brains of Alzheimer's disease and Nasu-Hakola disease2017

    • Author(s)
      Satoh J, Kino Y, Yanaizu M, Tosaki Y, Sakai K, Ishida T, Saito Y
    • Journal Title

      Intractable & Rare Diseases Research

      Volume: 6 Issue: 4 Pages: 262-268

    • DOI

      10.5582/irdr.2017.01073

    • NAID

      130006252922

    • ISSN
      2186-361X, 2186-3644
    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Gastric and intestinal proteases resistance of chicken acidic chitinase nominates chitin-containing organisms for alternative whole edible diets for poultry.2017

    • Author(s)
      Tabata, E., Kashimura, A., Wakita, S., Ohno, M., Sakaguchi, M., Sugahara, Y., Kino, Y., Matoska, V., Bauer, P.O. and Oyama, F.
    • Journal Title

      Sci. Rep.

      Volume: 7 Issue: 1 Pages: 6662-6662

    • DOI

      10.1038/s41598-017-07146-3

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] FUS/TLS acts as an aggregation-dependent modifier of polyglutamine disease model mice.2016

    • Author(s)
      Kino Y, Washizu C, Kurosawa M, Yamada M, Doi H, Takumi T, Adachi H, Katsuno M, Sobue G, Hicks GG, Hattori N, Shimogori T, Nukina N.
    • Journal Title

      Sci Rep.

      Volume: 6 Issue: 1 Pages: 35236-35236

    • DOI

      10.1038/srep35236

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] In vitroおよび細胞内における蛍光性アプタマーを用いたリピートRNAの検出2019

    • Author(s)
      紀嘉浩、正木泰行、河合美南、佐藤準一
    • Organizer
      第42回日本神経科学大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] GAジペプチドリピートおよびポリグルタミンと相互作用するタンパク質の解析2019

    • Author(s)
      河合美南、紀嘉浩、佐藤準一
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] RNA biology of neurodegenerative diseases: Repeat expansion, splicing, and Alzheimer’s risk factors2019

    • Author(s)
      Yoshihiro Kino
    • Organizer
      35th International Annual Meeting in Pharmaceutical Sciences and CU-MPU International Collaborative Research Conference
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] GGGGCCリピート由来細胞内凝集物の相互作用分子2018

    • Author(s)
      紀嘉浩、河合美南、正木泰行、佐藤準一
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] 7.蛍光性アプタマーを用いた神経疾患関連リピートRNAの可視化2017

    • Author(s)
      紀嘉浩、正木泰行、滝谷美香、佐藤準一
    • Organizer
      第40回日本分子生物学会年会
    • Related Report
      2017 Research-status Report
  • [Presentation] 6.那須ハコラ病の原因となるTREM2スプライス部位変異に対する治療分子2017

    • Author(s)
      紀嘉浩、柳津茂慧、佐藤準一
    • Organizer
      第40回日本神経科学大会
    • Related Report
      2017 Research-status Report
  • [Presentation] RNA結合タンパク質FUS/TLSの機能低下と神経疾患2017

    • Author(s)
      紀嘉浩
    • Organizer
      第19回応用薬理シンポジウム
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] Identification of proteins sequestered by dipeptide repeat aggregates associated with ALS/FTD2016

    • Author(s)
      Kino Y, Takitani M, Miyoshi J, Satoh J
    • Organizer
      第39回日本神経科学大会
    • Place of Presentation
      パシフィコ横浜
    • Related Report
      2016 Research-status Report
  • [Book] Myotonic Dystrophy (edited by ed by Takahashi MP, Matsumura T)2018

    • Author(s)
      Kino Y, Satoh J, Ishiura S
    • Publisher
      Springer, Singapore
    • ISBN
      9789811305078
    • Related Report
      2018 Research-status Report

URL: 

Published: 2016-04-21   Modified: 2021-02-19  

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