TDP-43 self-assembly is regulated by its disordered NLS-region

Authors

Hutten, S., Pekbilir, E., Bourgeois, B., Ping, X., Rickert, C., Kuhr, N., Knabe, N., Mosna, S., Madl, T., Stelzl, L. S., Dormann, D.

Abstract

Cytosolic inclusions of the RNA-binding protein TDP-43 are a pathological hallmark of several neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia. Cellular or animal model systems often use TDP-43 mutated in its nuclear localization signal (NLS) to study its cytosolic mislocalization and aggregation. Here we show that the disordered NLS-region, in particular the basic amino acids, are crucial for self-assembly of full-length TDP-43 across size scales, ranging from small clusters to visible condensates and aggregates. Molecular dynamics simulations and NMR studies suggest that the NLS-region engages in inter-chain interactions with C-terminal aromatic residues as well as RRM1 and NTD interactions. We further demonstrate that a minimal NLS mutation (K82A) preserves TDP-43 condensation in vitro and in cells, while commonly used NLS mutations yield partially or strongly reduced self-assembly behaviors. Our data highlight TDP-43 K82A as ideal model system to study cytosolic TDP-43 aggregation in cell and animal models.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 11 Jun 2026.

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