AUTHOR=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 

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

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=10

YEAR=2023

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2023.1148302

DOI=10.3389/fmolb.2023.1148302

ISSN=2296-889X

ABSTRACT=<p>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<sub>300–414</sub>), TDP-11 (TDP-43<sub>300–399</sub>), and TDP-10 (TDP-43<sub>314–414</sub>), 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.</p>