Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates by Xiao Yan,1 David Kuster,1,10 zamat Rizuan,3 Titus M. FraSzu-Huan Wang,5 JayakrishNicolas L. Fawzi,5 Dennis W. 1Max Planck Institute of Molecul instant download

Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates by Xiao Yan,1 David Kuster,1,10 zamat Rizuan,3 Titus M. FraSzu-Huan Wang,5 JayakrishNicolas L. Fawzi,5 Dennis W. 1Max Planck Institute of Molecul instant download

SUMMARYCytosolic aggregation of the nuclear protein TAR DNA-binding protein 43 (TDP-43) is associated with manyneurodegenerative diseases, but the triggers for TDP-43 aggregation are still debated. Here, we demonstratethat TDP-43 aggregation requires a double event. One is up-concentration in stress granules beyond athreshold, 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 transition intopathological aggregates. Intra-condensate demixing of TDP-43 is observed in iPS-motor neurons, a diseasemouse model, and patient samples. 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 suggest that up-concentration insidecondensates followed by intra-condensate demixing could be a general pathway for protein aggregation.