Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates. Academic Article uri icon


  • Cytosolic aggregation of the nuclear protein TDP-43 is associated with many neurodegenerative diseases, but the triggers for TDP-43 aggregation are still debated. Here, we demonstrate that TDP-43 aggregation requires a double event. One is up-concentration in stress granules beyond a threshold, and the other is oxidative stress. These two events collectively induce intra-condensate demixing, giving rise to a dynamic TDP-43 enriched phase within stress granules, which subsequently transitions into pathological aggregates. Mechanistically, intra-condensate demixing is triggered by local unfolding of the RRM1 domain for intermolecular disulfide bond formation and by increased hydrophobic patch interactions in the C-terminal domain. By engineering TDP-43 variants resistant to intra-condensate demixing, we successfully eliminate pathological TDP-43 aggregates in cells. We conclude that up-concentration inside condensates and simultaneous exposure to environmental stress could be a general pathway for protein aggregation, with intra-condensate demixing constituting a key intermediate step.

published proceedings

  • bioRxiv

altmetric score

  • 14.7

author list (cited authors)

  • Yan, X., Kuster, D., Mohanty, P., Nijssen, J., Pombo-Garca, K., Rizuan, A., ... Hyman, A. A.

citation count

  • 2

complete list of authors

  • Yan, Xiao||Kuster, David||Mohanty, Priyesh||Nijssen, Jik||Pombo-GarcĂ­a, Karina||Rizuan, Azamat||Franzmann, Titus M||Sergeeva, Aleksandra||Passos, Patricia M||George, Leah||Wang, Szu-Huan||Shenoy, Jayakrishna||Danielson, Helen L||Honigmann, Alf||Ayala, Yuna M||Fawzi, Nicolas L||Mittal, Jeetain||Alberti, Simon||Hyman, Anthony A

publication date

  • January 2024