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

Author information

Affiliations

  • 1. 1] Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang District, Taipei 115, Taiwan [2] Institute of Bioinformatics and Structural Biology, National Tsing Hua University, 101, Kuang fu Road, Section 2, Hsinchu 30013, Taiwan.
      Authors
    • Fang YS 1
    • Chen YR 1
    (2 authors)
  • 2. 1] Institute of Clinical Medicine, National Cheng Kung University, 1, University Road, Tainan 701, Taiwan [2] Institute of Basic Medical Science, National Cheng Kung University, 1, University Road, Tainan 701, Taiwan.
      Authors
    • Tsai KJ 2
    • Wu CC 2
    (2 authors)
  • 3. Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang District, Taipei 115, Taiwan.
      Authors
    • Chang YJ 3
    (1 author)
  • 4. Department of Pathology and Laboratory Medicine, Alzheimer's Disease Center, University of California Davis Medical Center, 2805 50th Street, Sacramento, California 95817, USA.
      Authors
    • Kao P 4
    • Woods R 4
    • Jin LW 4
    (3 authors)
  • 5. Institute of Molecular Biology, Academia Sinica, 128, Academia Road, Section 2, Nankang District, Taipei 115, Taiwan.
      Authors
    • Kuo PH 5
    • Yuan HS 5
    (2 authors)
    • Show all (9)

ORCIDs linked to this article

Nature Communications, 12 Sep 2014, 5:4824
https://doi.org/10.1038/ncomms5824 PMID: 25215604 

Abstract 

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.

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Read article at publisher's site: https://doi.org/10.1038/ncomms5824

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    Funding 

    Funders who supported this work.

    NIA NIH HHS (1)