Structural polymorphism of the low-complexity C-terminal domain of TDP-43 amyloid aggregates revealed by solid-state NMR
Jayakrishna Shenoy, Alons Lends, Mélanie Berbon, Muhammed Bilal, Nadia El Mammeri, Mathilde Bertoni, Ahmad Saad, Estelle Morvan, Axelle Grélard, Sophie Lecomte, François‐Xavier Theillet, Alexander K. Buell, Brice Kauffmann, Birgit Habenstein, Antoine Loquet
Abstract
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-43 300–414 ), TDP-11 (TDP-43 300–399 ), and TDP-10 (TDP-43 314–414 ), 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.