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

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-comp...

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Published in:Frontiers in molecular biosciences 2023-03, Vol.10, p.1148302-1148302
Main Authors: Shenoy, Jayakrishna, Lends, Alons, Berbon, Mélanie, Bilal, Muhammed, El Mammeri, Nadia, Bertoni, Mathilde, Saad, Ahmad, Morvan, Estelle, Grélard, Axelle, Lecomte, Sophie, Theillet, François-Xavier, Buell, Alexander K, Kauffmann, Brice, Habenstein, Birgit, Loquet, Antoine
Format: Article
Language:English
Subjects:
amyloid
amyotrophic lateral sclerosis
frontotemporal dementia
Life Sciences
Molecular Biosciences
polymorphism
solid-state NMR
TDP-43
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Summary: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-43 ), TDP-11 (TDP-43 ), and TDP-10 (TDP-43 ), 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.
ISSN:2296-889X
2296-889X
DOI:10.3389/fmolb.2023.1148302