Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

Yu Sheng Fang, Kuen Jer Tsai, Yu Jen Chang, Patricia Kao, Rima Woods, Pan Hsien Kuo, Cheng Chun Wu, Jhih Ying Liao, Shih Chieh Chou, Vinson Lin, Lee Way Jin, Hanna S. Yuan, Irene H. Cheng, Pang Hsien Tu, Yun Ru Chen

研究成果: Article同行評審

90 引文 斯高帕斯(Scopus)

摘要

Proteinaceous inclusions are common hallmarks of many neurodegenerative diseases. TDP-43 proteinopathies, consisting of several neurodegenerative diseases, including frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS), are characterized by inclusion bodies formed by polyubiquitinated and hyperphosphorylated full-length and truncated TDP-43. The structural properties of TDP-43 aggregates and their relationship to pathogenesis are still ambiguous. Here we demonstrate that the recombinant full-length human TDP-43 forms structurally stable, spherical oligomers that share common epitopes with an anti-amyloid oligomer-specific antibody. The TDP-43 oligomers are stable, have exposed hydrophobic surfaces, exhibit reduced DNA binding capability and are neurotoxic in vitro and in vivo. Moreover, TDP-43 oligomers are capable of cross-seeding Alzheimer's amyloid-β to form amyloid oligomers, demonstrating interconvertibility between the amyloid species. Such oligomers are present in the forebrain of transgenic TDP-43 mice and FTLD-TDP patients. Our results suggest that aside from filamentous aggregates, TDP-43 oligomers may play a role in TDP-43 pathogenesis.

原文English
文章編號4824
期刊Nature communications
5
DOIs
出版狀態Published - 2014

All Science Journal Classification (ASJC) codes

  • 化學 (全部)
  • 生物化學、遺傳與分子生物學 (全部)
  • 物理與天文學 (全部)

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