Structure of pathological TDP-43 filaments from ALS with FTLD.
Structure of pathological TDP-43 filaments from ALS with FTLD.
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DOI：
10.1038/s41586-021-04199-3
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发表时间：
2022-01
期刊：
影响因子：
64.8
通讯作者：
Ryskeldi-Falcon B
中科院分区：
文献类型：
--
作者：
Arseni D;Hasegawa M;Murzin AG;Kametani F;Arai M;Yoshida M;Ryskeldi-Falcon B
43 kDa交互反应dna结合蛋白（TDP-43）在神经元和神经胶质中的异常聚集是神经退行性疾病肌萎缩性侧索硬化症（ALS）和多种形式的额颞叶变性（FTLD）的决定性病理标志。它在其他疾病中也很常见，包括阿尔茨海默氏症和帕金森症。目前还没有改善疾病的治疗方法，早期诊断也不可能。病理TDP-43聚集体的结构尚不清楚。我们使用电子冷冻显微镜来确定一个患有ALS合并FTLD的个体的额叶和运动皮层中聚集的TDP-43的结构，以及另一个患有相同诊断的个体的额叶皮层。在大脑区域和个体中都发现了由单一原丝组成的相同的淀粉样纤维结构。有序丝芯跨越TDP-43低复杂性结构域282 ~ 360残基，采用新颖的双螺旋褶皱，与体外形成的TDP-43丝芯没有相似之处。丰富的甘氨酸和中性极性残基促进了大量的转变，限制了β-链的长度，导致缺乏与交叉β淀粉样蛋白结构相关的β-片堆积。残基的不均匀分布产生了结构和化学上不同的表面，这些表面面对外部密度并暗示可能的配体结合位点。这项工作增强了我们对ALS和FTLD的分子发病机制的理解，并为开发靶向聚集TDP-43的诊断和治疗药物提供了信息。
The abnormal aggregation of transactive response DNA-binding protein of 43 kDa (TDP-43) in neurons and glia is the defining pathological hallmark of neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and multiple forms of frontotemporal lobar degeneration (FTLD) . It is also common in other diseases, including Alzheimer's and Parkinson's. No disease-modifying therapies exist and early diagnosis is not possible. The structures of pathological TDP-43 aggregates are unknown. We used electron cryo-microscopy to determine the structures of aggregated TDP-43 in the frontal and motor cortices of an individual that succumbed to ALS with FTLD, as well as from the frontal cortex of a second individual with the same diagnosis. An identical amyloid-like filament structure comprising a single protofilament was found in both brain regions and individuals. The ordered filament core spans residues 282 to 360 in the TDP-43 low-complexity domain and adopts a novel double-spiral-shaped fold, which shows no similarity to those of TDP-43 filaments formed in vitro . An abundance of glycine and neutral polar residues facilitates numerous turns and restricts β-strand length, resulting in an absence of β-sheet stacking associated with cross-β amyloid structure. An uneven distribution of residues gives rise to structurally and chemically distinct surfaces, which face external densities and suggest possible ligand binding sites. This work enhances our understanding of the molecular pathogenesis of ALS and FTLD and informs the development of diagnostic and therapeutic agents targeting aggregated TDP-43.
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