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Brain Proteinopathy 2014
Brain Proteinopathy 2014

開催日 2014/9/11
時間 17:00 - 19:00
会場 Room E(301)
Chairperson(s) 田中 元雅 / Motomasa Tanaka (独立行政法人理化学研究所 脳科学総合研究センター タンパク質構造疾患研究チーム / Laboratory for Protein Conformation Diseases, RIKEN Brain Science Institute, Japan)
貫名 信行 / Nobuyuki Nukina (順天堂大学大学院医学研究科 神経変性疾患病態治療探索講座 / Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Japan)

Prion-like properties of pathological insoluble TDP-43 in diseased brains

  • S1-E-3-1
  • 野中 隆 / Takashi Nonaka:1 鈴掛 雅美 / Masami Masuda-Suzukake:1 新井 哲明 / Tetsuaki Arai:2 吉田 眞理 / Mari Yoshida:3 村山 繁雄 / Shigeo Murayama:4 マン デービッド / David Mann:5 秋山 治彦 / Haruhiko Akiyama:1 長谷川 成人 / Masato Hasegawa:1 
  • 1:東京都医学総合研究所 / Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan 2:筑波大学 / Univ. of Tsukuba, Ibaraki, Japan 3:愛知医大 / Aichi Medical Univ., Aichi, Japan 4:東京都健康長寿医療センター研究所 / Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 5:Univ. of Manchester, UK / Univ. of Manchester, Manchester, UK 

TAR-DNA binding protein of 43 kDa (TDP-43) is the major component protein of ubiquitin-positive inclusions observed in brains of patients with frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). Here we report a seed-dependent TDP-43 aggregation model using detergent-insoluble TDP-43 prepared from diseased brains and the characterization of Prion-like properties of insoluble TDP-43.
When insoluble TDP-43 from ALS or FTLD-TDP brains was introduced into SH-SY5Y cells expressing TDP-43, round inclusions composed of phosphorylated and ubiquitinated TDP-43 were observed. Biochemical fractionation revealed the presence of Sarkosyl-insoluble TDP-43 detectable with anti-phospho TDP-43 antibody. We found that the heat treatment of insoluble TDP-43 impaired its ability to seed for aggregation, while it functioned as seeds even after the protease treatment with Proteinase K. Insoluble fraction from cells harboring TDP-43 aggregates also triggered intracellular TDP-43 aggregation. Furthermore, phosphorylated TDP-43 aggregates were shown to propagate from cell to cell via exosome. These results indicates that TDP-43 aggregates have surprising properties similar to those of pathogenic prion protein.
This unique seeding model reproduces characteristic features of affected neurons in brains with TDP-43 proteinopathy, and is expected to be useful for screening of drug candidates for treatment or prevention of these diseases.

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