Cryo-EM structures of four polymorphic TDP-43 amyloid cores
Cryo-EM structures of four polymorphic TDP-43 amyloid cores
复制标题
DOI：
10.1038/s41594-019-0248-4
复制
发表时间：
2019-07-01
影响因子：
16.8
通讯作者：
Eisenberg, David S.
中科院分区：
文献类型：
--
作者：
Cao, Qin;Boyer, David R.;Eisenberg, David S.
DNA和RNA加工蛋白TDP-43经历功能性和致病性聚集。功能性TDP-43聚集体形成可逆的瞬时物质，如核体、应激颗粒和肌颗粒。致病的、不可逆的TDP-43聚集体在肌萎缩侧索硬化症和其他神经退行性疾病中形成。在这里，我们发现TDP-43原纤维的特征，通过确定两个片段的结构，赋予可逆性和不可逆性，这两个片段被报道为人类TDP-43聚集的致病核心：SegA（残基311-360），其形成三种多晶型物，均具有匕首形折叠;和SegB A315 E（残基286-331含有肌萎缩性侧索硬化症遗传突变A315 E），其形成R形折叠。能量分析表明，匕首形的多晶型物代表不可逆的原纤维结构，而SegB多晶型物可能参与可逆和不可逆的原纤维。我们的结构揭示了TDP-43的多态性，并表明A315 E突变如何将R型多晶型转化为增强病理学的不可逆形式。
The DNA and RNA processing protein TDP-43 undergoes both functional and pathogenic aggregation. Functional TDP-43 aggregates form reversible, transient species such as nuclear bodies, stress granules, and myo-granules. Pathogenic, irreversible TDP-43 aggregates form in amyotrophic lateral sclerosis and other neurodegenerative conditions. Here we find the features of TDP-43 fibrils that confer both reversibility and irreversibility by determining structures of two segments reported to be the pathogenic cores of human TDP-43 aggregation: SegA (residues 311-360), which forms three polymorphs, all with dagger-shaped folds; and SegB A315E (residues 286-331 containing the amyotrophic lateral sclerosis hereditary mutation A315E), which forms R-shaped folds. Energetic analysis suggests that the dagger-shaped polymorphs represent irreversible fibril structures, whereas the SegB polymorph may participate in both reversible and irreversible fibrils. Our structures reveal the polymorphic nature of TDP-43 and suggest how the A315E mutation converts the R-shaped polymorph to an irreversible form that enhances pathology.