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 and Yun-Ru Chen ()
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Yu-Sheng Fang: Genomics Research Center, Academia Sinica
Kuen-Jer Tsai: Institute of Clinical Medicine, National Cheng Kung University
Yu-Jen Chang: Genomics Research Center, Academia Sinica
Patricia Kao: Alzheimer’s Disease Center, University of California Davis Medical Center
Rima Woods: Alzheimer’s Disease Center, University of California Davis Medical Center
Pan-Hsien Kuo: Institute of Molecular Biology, Academia Sinica
Cheng-Chun Wu: Institute of Clinical Medicine, National Cheng Kung University
Jhih-Ying Liao: Institute of Brain Science, School of Medicine, National Yang Ming University
Shih-Chieh Chou: Genomics Research Center, Academia Sinica
Vinson Lin: National Taiwan University
Lee-Way Jin: Alzheimer’s Disease Center, University of California Davis Medical Center
Hanna S. Yuan: Institute of Molecular Biology, Academia Sinica
Irene H. Cheng: Institute of Brain Science, School of Medicine, National Yang Ming University
Pang-Hsien Tu: Institute of Biomedical Sciences, Academia Sinica
Yun-Ru Chen: Genomics Research Center, Academia Sinica

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5824

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