英国MRC分子生物学实验室Benjamin Ryskeldi-Falcon课题组揭示来自具有额颞叶退化（FTLD）的肌萎缩侧索硬化症（ALS）患者的病理性TDP-43丝结构。2021年12月8日，国际知名学术期刊《自然》在线发表了这一成果。

Author: Arseni, Diana, Hasegawa, Masato, Murzin, Alexey G., Kametani, Fuyuki, Arai, Makoto, Yoshida, Mari, Ryskeldi-Falcon, Benjamin

Issue&Volume: 2021-12-08

Abstract: The abnormal aggregation of TAR DNA-binding protein 43kDa (TDP-43) in neurons and glia is the defining pathological hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and multiple forms of frontotemporal lobar degeneration (FTLD)1,2. It is also common in other diseases, including Alzheimer’s and Parkinson’s. No disease-modifying therapies exist for these conditions and early diagnosis is not possible. The structures of pathological TDP-43 aggregates are unknown. Here we used cryo-electron microscopy to determine the structures of aggregated TDP-43 in the frontal and motor cortices of an individual who had ALS with FTLD and 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 282–360 in the TDP-43 low-complexity domain and adopts a previously undescribed double-spiral-shaped fold, which shows no similarity to those of TDP-43 filaments formed in vitro3,4. An abundance of glycine and neutral polar residues facilitates numerous turns and restricts β-strand length, which results in an absence of β-sheet stacking that is associated with cross-β amyloid structure. An uneven distribution of residues gives rise to structurally and chemically distinct surfaces that 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 that target aggregated TDP-43.

DOI: 10.1038/s41586-021-04199-3

Source: https://www.nature.com/articles/s41586-021-04199-3