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.
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.
Nat Commun. 2014 Sep 12;5:4824. doi: 10.1038/ncomms5824.
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.
蛋白包涵体是许多神经退行性疾病的共同特征。TDP-43 蛋白病由几种神经退行性疾病组成，包括额颞叶痴呆（FTLD）和肌萎缩性侧索硬化症（ALS），其特征是由多聚泛素化和过度磷酸化的全长和截断的 TDP-43 形成的包含体。TDP-43 聚集物的结构特性及其与发病机制的关系仍不清楚。在这里，我们证明重组全长人 TDP-43 形成结构稳定的球形寡聚体，与抗淀粉样寡聚体特异性抗体具有共同的表位。TDP-43 寡聚体稳定，具有暴露的疏水面，表现出降低的 DNA 结合能力，并且在体外和体内具有神经毒性。此外，TDP-43 寡聚体能够交叉引发阿尔茨海默病淀粉样蛋白-β形成淀粉样寡聚体，证明了淀粉样物质之间的可转换性。这种寡聚体存在于转染 TDP-43 小鼠和 FTLD-TDP 患者的前脑中。我们的结果表明，除了纤维状聚集物外，TDP-43 寡聚体可能在 TDP-43 发病机制中起作用。
