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英国MRC分子生物学实验室Benjamin Ryskeldi-Falcon团队发现，TDP-43在A型FTLD-TDP中形成具有独特折叠的淀粉样蛋白丝。相关论文于2023年8月2日在线发表于国际学术期刊《自然》。

研究人员表示，TAR DNA结合蛋白43（TDP-43）在神经元和神经胶质细胞中的异常组装是几乎所有肌萎缩性脊髓侧索硬化症（ALS）病例和大约一半额颞叶变性（FTLD）病例的特征。编码TDP-43的基因TARDBP发生显性遗传的错义突变，促进了TDP-43的组装并导致ALS和FTLD。至少有四种类型（A-D）的前颞叶痴呆伴TDP-43病理（FTLD-TDP）是根据组装的TDP-43在大脑中的不同分布来定义的，并与前颞叶痴呆的不同临床表现相关。研究人员曾用冷冻电镜显示，TDP-43在ALS和B型FTLD-TDP中组装成淀粉样蛋白丝。然而，在无ALS的FTLD中，TDP-43的组装结构仍然未知。

研究人员报告了三位最常见的FTLD-TDP A 型患者大脑中TDP-43的冷冻电镜结构。TDP-43形成的淀粉样蛋白丝具有一种新的折叠，这种折叠在不同的个体中是相同的，这表明这种折叠可能是A型FTLD-TDP的特征。这种折叠类似于人字形徽章，不同于ALS和B型FTLD-TDP的双螺旋形折叠，从而确定了不同神经退行性疾病具有不同的TDP-43丝状折叠特征。

这些结构与质谱分析相结合，确定了组装后的TDP-43的两种新的翻译后修饰（R293的瓜氨酸化和单甲基化），并表明它们可能促进了丝状物的形成和观察到的单个丝状物的结构变化。A型FTLD-TDP的TDP-43细丝结构将指导TDP-43组装的机理研究，以及TDP-43蛋白病的诊断和治疗化合物的开发。

附：英文原文

Title: TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP

Author: Arseni, Diana, Chen, Renren, Murzin, Alexey G., Peak-Chew, Sew Y., Garringer, Holly J., Newell, Kathy L., Kametani, Fuyuki, Robinson, Andrew C., Vidal, Ruben, Ghetti, Bernardino, Hasegawa, Masato, Ryskeldi-Falcon, Benjamin

Issue&Volume: 2023-08-02

Abstract: The abnormal assembly of TAR DNA-binding protein 43 (TDP-43) in neuronal and glial cells characterizes nearly all cases of amyotrophic lateral sclerosis (ALS) and around half of cases of frontotemporal lobar degeneration (FTLD)1,2. A causal role for TDP-43 assembly in neurodegeneration is evidenced by dominantly inherited missense mutations in TARDBP, the gene encoding TDP-43, that promote assembly and give rise to ALS and FTLD3,4,5,6,7. At least four types (A–D) of FTLD with TDP-43 pathology (FTLD-TDP) are defined by distinct brain distributions of assembled TDP-43 and are associated with different clinical presentations of frontotemporal dementia8. We previously showed, using cryo-electron microscopy, that TDP-43 assembles into amyloid filaments in ALS and type B FTLD-TDP9. However, the structures of assembled TDP-43 in FTLD without ALS remained unknown. Here we report the cryo-electron microscopy structures of assembled TDP-43 from the brains of three individuals with the most common type of FTLD-TDP, type A. TDP-43 formed amyloid filaments with a new fold that was the same across individuals, indicating that this fold may characterize type A FTLD-TDP. The fold resembles a chevron badge and is unlike the double-spiral-shaped fold of ALS and type B FTLD-TDP, establishing that distinct filament folds of TDP-43 characterize different neurodegenerative conditions. The structures, in combination with mass spectrometry, led to the identification of two new post-translational modifications of assembled TDP-43, citrullination and monomethylation of R293, and indicate that they may facilitate filament formation and observed structural variation in individual filaments. The structures of TDP-43 filaments from type A FTLD-TDP will guide mechanistic studies of TDP-43 assembly, as well as the development of diagnostic and therapeutic compounds for TDP-43 proteinopathies.

DOI: 10.1038/s41586-023-06405-w

Source: https://www.nature.com/articles/s41586-023-06405-w

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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