• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

The mechanism of cytotoxicity from ALS-linked Profilin 1 mutations

Research Project

Project/Area Number 15K18370
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Nerve anatomy/Neuropathology
Research InstitutionTokyo Metropolitan Institute of Medical Science

Principal Investigator

TANAKA Yoshinori  公益財団法人東京都医学総合研究所, 認知症・高次脳機能研究分野, 研究員 (00747933)

Co-Investigator(Renkei-kenkyūsha) HASEGAWA Masato  公益財団法人東京都医学総合研究所, 認知症高次脳機能研究分野, 分野長 (10251232)
NONAKA Takashi  公益財団法人東京都医学総合研究所, 認知症高次脳機能研究分野, 副参事研究員 (30356258)
KAMETANI Fuyuki  公益財団法人東京都医学総合研究所, 認知症高次脳機能研究分野, 主席研究員 (70186013)
SUZUKI Genjiro  公益財団法人東京都医学総合研究所, 認知症高次脳機能研究分野, 主席研究員 (60466034)
HOSOKAWA Masato  公益財団法人東京都医学総合研究所, 認知症高次脳機能研究分野, 主席研究員 (00435116)
Project Period (FY) 2015-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
KeywordsProfilin1 / TDP-43 / ALS / mutation / aggresome / LC3 / seeding / prion / プロフィリン1 / アグリソーム / 筋萎縮性側索硬化症 / プリオン
Outline of Final Research Achievements

The nuclear protein TDP-43 accumulates at the cytoplasm of motor neurons, as a pathological form, in the patients of amyotrophic lateral sclerosis (ALS). As the role of TDP-43 in the nucleus is essential, the accumulation of pathological TDP-43 is identified as a cause of ALS. In the present study, we investigated the effect of ALS-linked PFN1 gene mutations, a cause of familial ALS characteristic of TDP-43 accumulation, on the accumulation of TDP-43 using cultured cells. The cells expressing mutant PFN1 harbored PFN1 aggregates, and those sequestered TDP-43. Furthermore, TDP-43 sequestered into PFN1 aggregates was partly converted into the pathological form of TDP-43 that promotes TDP-43 accumulation like a pathological prion.

Report

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

    (18 results)

All 2017 2016 2015 Other

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 3 results,  Acknowledgement Compliant: 3 results) Presentation (12 results) (of which Int'l Joint Research: 5 results,  Invited: 1 results) Remarks (2 results)

  • [Journal Article] Progranulin regulates lysosomal function and biogenesis through acidification of lysosomes.2017

    • Author(s)
      Tanaka Y, Suzuki G, Matsuwaki T, Hosokawa M, Serrano G, Beach TG, Yamanouchi K, Hasegawa M, Nishihara M.
    • Journal Title

      Human Molecular Genetics

      Volume: 26 Pages: 969-988

    • DOI

      10.1093/hmg/ddx011

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Profilin 1 mutants form aggregates that induce accumulation of prion-like TDP-43.2016

    • Author(s)
      Tanaka Y, Hasegawa M
    • Journal Title

      Prion

      Volume: 10 Issue: 4 Pages: 283-289

    • DOI

      10.1080/19336896.2016.1207033

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Gain-of-function profilin 1 mutations linked to familial amyotrophic lateral sclerosis cause seed-dependent intracellular TDP-43 aggregation.2016

    • Author(s)
      Tanaka Y, Nonaka T, Suzuki G, Kametani F, Hasegawa M.
    • Journal Title

      Human Molecular Genetics

      Volume: 25 Issue: 7 Pages: 1420-33

    • DOI

      10.1093/hmg/ddw024

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Phosphorylation of TAR DNA-binding Protein of 43 kDa (TDP-43) by Truncated Casein Kinase 1δ Triggers Mislocalization and Accumulation of TDP-43.2016

    • Author(s)
      Nonaka T, Suzuki G, Tanaka Y, Kametani F, Hirai S, Okado H, Miyashita T, Saitoe M, Akiyama H, Masai H, Hasegawa M.
    • Journal Title

      The journal of Biological Chemistry

      Volume: 291 Issue: 11 Pages: 5473-83

    • DOI

      10.1074/jbc.m115.695379

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Mutations in the PFN1 gene induce degenerative changes through aggregation of both mutant PFN1 and TDP-43.2016

    • Author(s)
      Tanaka Y, Nonaka T, Suzuki G, Kametani F, Hasegawa M.
    • Organizer
      第14回医学研国際シンポジウム
    • Place of Presentation
      東京都医学総合研究所 (東京都世田谷区)
    • Year and Date
      2016-06-30
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] プログラニュリンはリソソームの酸性化を促進する2016

    • Author(s)
      田中良法
    • Organizer
      第1回プログラニュリン研究会
    • Place of Presentation
      岐阜スカイウイング37(岐阜県岐阜市)
    • Year and Date
      2016-05-28
    • Related Report
      2015 Research-status Report
  • [Presentation] ALSの原因となるプロフィリン1変異は機能獲得によりTDP-43の蓄積を誘起する2016

    • Author(s)
      田中良法、野中隆、鈴木元治郎、亀谷富由樹、長谷川成人
    • Organizer
      H27年度 ALS病態解明班 成果報告会
    • Place of Presentation
      都市センターホテル(東京都千代田区)
    • Year and Date
      2016-01-26
    • Related Report
      2015 Research-status Report
  • [Presentation] 原因タンパク質から探るFTLD/ALSの発症機構2016

    • Author(s)
      田中良法
    • Organizer
      第57回獣医学特論
    • Place of Presentation
      東京大学弥生講堂(東京都文京区)
    • Year and Date
      2016-01-15
    • Related Report
      2015 Research-status Report
    • Invited
  • [Presentation] Gain-of-function Profilin 1 mutations linked to familial amyotrophic lateral sclerosis cause intracellular TDP-43 aggregation.2016

    • Author(s)
      Tanaka Y, Nonaka T.
    • Organizer
      脳内環境平成27年度冬の班会議
    • Place of Presentation
      京都大学芝蘭会館(京都府京都市)
    • Year and Date
      2016-01-08
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] Progranulin overexpression decrease levels of the matured form of cathepsin D due to enhancement of lysosomal acidificaition.2016

    • Author(s)
      Tanaka Y, Suzuki G, Hosokawa M, Kametani F, Hasegawa M, Nishihara M.
    • Organizer
      第39回日本神経科学大会
    • Place of Presentation
      パシフィコ横浜 (神奈川県横浜市)
    • Related Report
      2016 Annual Research Report
  • [Presentation] プログラニュリンはリソソームの酸性化を促進する2016

    • Author(s)
      田中良法
    • Organizer
      第1回プログラニュリン研究会
    • Place of Presentation
      岐阜スカイウイング37 (岐阜県岐阜市)
    • Related Report
      2016 Annual Research Report
  • [Presentation] Mutations in the PFN1 gene induce degenerative changes through aggregation of both mutant PFN1 and TDP-43.2015

    • Author(s)
      Tanaka Y, Nonaka T, Suzuki G, Kametani F, Hasegawa M.
    • Organizer
      Neuroscience 2015, SfN's 45th annual meeting
    • Place of Presentation
      シカゴ(米国)
    • Year and Date
      2015-10-17
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] Gain-of-function Profilin 1 mutations linked to familial amyotrophic lateral sclerosis cause intracellular TDP-43 aggregation.2015

    • Author(s)
      Tanaka Y, Nonaka T, Suzuki G, Kametani F, Hasegawa M.
    • Organizer
      Brain Protein Aging and Dementia Control, 1st International Symposium 2015
    • Place of Presentation
      野依記念学術交流館(愛知県名古屋市)
    • Year and Date
      2015-10-09
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] ALSの原因となるプロフィリン1変異はTDP-43の凝集を誘起する2015

    • Author(s)
      田中良法、野中隆、鈴木元治郎、亀谷富由樹、長谷川成人
    • Organizer
      第41回日本認知症学会
    • Place of Presentation
      リンクステーションホテル青森(青森県青森市)
    • Year and Date
      2015-10-03
    • Related Report
      2015 Research-status Report
  • [Presentation] ALSの原因となるプロフィリン1変異は機能獲得によりTDP-43の凝集を誘起する2015

    • Author(s)
      田中良法、野中隆、鈴木元治郎、亀谷富由樹、長谷川成人
    • Organizer
      認知症研究を知る若手研究者の集まり 2015
    • Place of Presentation
      ニューサンピア高崎(群馬県高崎市)
    • Year and Date
      2015-08-02
    • Related Report
      2015 Research-status Report
  • [Presentation] Progranulin mediates neurovascular protection via multiple therapeutic effects in experimental acute ischemic stroke.2015

    • Author(s)
      Kanazawa M, Kawamura K, Takahashi T, Miura M, Tanaka Y, Koyama M, Toriyabe M, Igarashi H, Nakada T, Nishihara M, Nishizawa M, Shimohata T.
    • Organizer
      Brain and Brain PET 2015
    • Place of Presentation
      バンクーバー(カナダ)
    • Year and Date
      2015-06-27
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Remarks] リソソームにおけるプログラニュリンの機能的役割を解明

    • URL

      http://www.igakuken.or.jp/topics/2017/0110.html

    • Related Report
      2016 Annual Research Report
  • [Remarks] プロフィリン1遺伝子(PFN1)変異によるALS発症機構

    • URL

      http://www.igakuken.or.jp/topics/2016/0128.html

    • Related Report
      2015 Research-status Report

URL: 

Published: 2015-04-16   Modified: 2018-03-22  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi