Cryo-EM observation of the amyloid key structure of polymorphic TDP-43 amyloid fibrils

Kartikay Sharma (), Fabian Stockert, Jayakrishna Shenoy, Mélanie Berbon, Muhammed Bilal Abdul-Shukkoor, Birgit Habenstein, Antoine Loquet, Matthias Schmidt and Marcus Fändrich
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Kartikay Sharma: Ulm University
Fabian Stockert: Ulm University
Jayakrishna Shenoy: University of Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, IECB
Mélanie Berbon: University of Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, IECB
Muhammed Bilal Abdul-Shukkoor: University of Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, IECB
Birgit Habenstein: University of Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, IECB
Antoine Loquet: University of Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, IECB
Matthias Schmidt: Ulm University
Marcus Fändrich: Ulm University

Nature Communications, 2024, vol. 15, issue 1, 1-8

Abstract: Abstract The transactive response DNA-binding protein-43 (TDP-43) is a multi-facet protein involved in phase separation, RNA-binding, and alternative splicing. In the context of neurodegenerative diseases, abnormal aggregation of TDP-43 has been linked to amyotrophic lateral sclerosis and frontotemporal lobar degeneration through the aggregation of its C-terminal domain. Here, we report a cryo-electron microscopy (cryo-EM)-based structural characterization of TDP-43 fibrils obtained from the full-length protein. We find that the fibrils are polymorphic and contain three different amyloid structures. The structures differ in the number and relative orientation of the protofilaments, although they share a similar fold containing an amyloid key motif. The observed fibril structures differ from previously described conformations of TDP-43 fibrils and help to better understand the structural landscape of the amyloid fibril structures derived from this protein.

Date: 2024
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DOI: 10.1038/s41467-023-44489-0

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