ALS-associated mutations reveal a conserved C-terminal self-assembly module in the TDP-43 low-complexity domain

Topic: Disease mechanisms in lab and animal studies

TAR DNA-binding protein 43 (TDP-43) is an RNA-binding protein whose low-complexity domain (LCD) mediates self-assembly, liquid-liquid phase separation, and pathological aggregation associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Previous studies have established the central ultraconserved region (UCR) of the LCD as a major determinant of TDP-43 self-association. However, the contribution of the evolutionarily conserved C-terminal region remains poorly understood. To identify LCD residues required for self-assembly, we systematically analyzed 47 ALS-associated substitutions distributed throughout the TDP-43 LCD using hydrogel-binding and thioflavin T (ThT) assays. Several ALS-associated substitutions within the C-terminal conserved region (CCR) markedly reduced hydrogel incorporation and impaired fibrillization. Similar assembly defects were observed for methionine-to-serine substitutions at two conserved CCR residues, M405 and M414. Furthermore, CCR-containing C-terminal fragments encompassing residues 360–414 or 379–414 formed ThT-positive fibrillar assemblies in vitro . The assembly kinetics exhibited a characteristic lag phase followed by rapid fluorescence growth, consistent with the formation of cross-β-rich assemblies. These findings identify the CCR as an additional conserved self-assembly module within the TDP-43 LCD and expand the prevailing UCR-centered model of TDP-43 assembly. The observation that multiple ALS-associated substitutions reduce rather than enhance self-association further raises the possibility that disruption of normal TDP-43 assembly contributes to disease pathogenesis.

Key findings

• TAR DNA-binding protein 43 (TDP-43) is an RNA-binding protein whose low-complexity domain (LCD) mediates self-assembly, liquid-liquid phase separation, and pathological aggregation associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
• These findings identify the CCR as an additional conserved self-assembly module within the TDP-43 LCD and expand the prevailing UCR-centered model of TDP-43 assembly.

Study details

• Participants47
• Evidence strengthLow

Read the original

• DOI: 10.64898/2026.10.09.756561
• Original source →

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@article{maita2026-e1e796ab,
  author  = {Maita, N. and Kim, S. and Kajino, Y. and Kato, M.},
  title   = {{ALS-associated mutations reveal a conserved C-terminal self-assembly module in the TDP-43 low-complexity domain}},
  journal = {bioRxiv},
  year    = {2026},
  doi     = {10.64898/2026.10.09.756561},
  url     = {https://doi.org/10.64898/2026.10.09.756561}
}

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