Structural polymorphism of the low-complexity C-terminal domain of TDP-43 amyloid aggregates revealed by solid-state NMR

Frontiers in Molecular Biosciences

Molecular Biosciences

Alexander K. Buell¹  François-Xavier Theillet²  Muhammed Bilal³  Mathilde Bertoni³  Alons Lends³  Mélanie Berbon³  Sophie Lecomte³  Axelle Grélard³  Nadia El Mammeri³  Antoine Loquet³  Jayakrishna Shenoy³  Ahmad Saad³  Birgit Habenstein³  Estelle Morvan⁴  Brice Kauffmann⁴ 

[1] Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark;Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, Gif-surYvette Cedex, France;University Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, IECB, Pessac, France;University Bordeaux, CNRS, INSERM, IECB, UAR 3033, Pessac, France;

关键词: TDP-43;    amyotrophic lateral sclerosis;    frontotemporal dementia;    amyloid;    polymorphism;    solid-state NMR;    low-complexity domain;   

DOI  :  10.3389/fmolb.2023.1148302

 received in 2023-01-19, accepted in 2023-03-17,  发布年份 2023

来源: Frontiers

【 摘 要 】

Aberrant aggregation of the transactive response DNA-binding protein (TDP-43) is associated with several lethal neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia. Cytoplasmic neuronal inclusions of TDP-43 are enriched in various fragments of the low-complexity C-terminal domain and are associated with different neurotoxicity. Here we dissect the structural basis of TDP-43 polymorphism using magic-angle spinning solid-state NMR spectroscopy in combination with electron microscopy and Fourier-transform infrared spectroscopy. We demonstrate that various low-complexity C-terminal fragments, namely TDP-13 (TDP-43300–414), TDP-11 (TDP-43300–399), and TDP-10 (TDP-43314–414), adopt distinct polymorphic structures in their amyloid fibrillar state. Our work demonstrates that the removal of less than 10% of the low-complexity sequence at N- and C-termini generates amyloid fibrils with comparable macroscopic features but different local structural arrangement. It highlights that the assembly mechanism of TDP-43, in addition to the aggregation of the hydrophobic region, is also driven by complex interactions involving low-complexity aggregation-prone segments that are a potential source of structural polymorphism.

【 授权许可】

Unknown   
Copyright © 2023 Shenoy, Lends, Berbon, Bilal, El Mammeri, Bertoni, Saad, Morvan, Grélard, Lecomte, Theillet, Buell, Kauffmann, Habenstein and Loquet.