Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates

Cytosolic aggregation of the nuclear protein TAR DNA-binding protein 43 (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 transition into pathological aggregates. Intra-condensate demixing of TDP-43 is observed in iPS-motor neurons, a disease mouse model, and patient samples. Mechanistically, intra-condensate demixing is…

• UD
  U.S. Department of Defense

  Award: W81XWH-20-1-0241
• EC
  European Commission
• DF
  Deutsche Forschungsgemeinschaft

  Award: 369799452
• K
  Körber-Stiftung
• M
  Max-Planck-Gesellschaft
• NS
  NOMIS Stiftung
• UO
  University of Science and Technology of China
• ER
  European Research Council

  Award: 725836
• NI
  National Institute on Aging
• NI
  National Institute of Neurological Disorders and Stroke

  Award: R01 NS114289
• CD
  Congressionally Directed Medical Research Programs