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 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 inside condensates followed by intra-condensate demixing could be a general pathway for protein aggregation.
Authors
- Yuna M. Ayala (ORCID: https://orcid.org/0000-0003-4688-6583)
- Jorge García Morato (ORCID: https://orcid.org/0000-0001-8061-7841)
- Simon Alberti (ORCID: https://orcid.org/0000-0003-4017-6505)
- Dennis W. Dickson (ORCID: https://orcid.org/0000-0001-7189-7917)
- Priyesh Mohanty (ORCID: https://orcid.org/0000-0003-3919-3527)
- Karina Pombo‐García (ORCID: https://orcid.org/0000-0002-2077-5909)
- Azamat Rizuan (ORCID: https://orcid.org/0000-0003-3590-0829)
- Szu‐Huan Wang (ORCID: https://orcid.org/0009-0009-8499-7066)
- Feilin Liu (ORCID: https://orcid.org/0000-0002-3830-4355)
- Helen L. Danielson
- David Kuster (ORCID: https://orcid.org/0000-0002-8157-9223)
- Alf Honigmann (ORCID: https://orcid.org/0000-0003-0475-3790)
- Titus M. Franzmann (ORCID: https://orcid.org/0000-0002-4281-7209)
- Busra Ozguney (ORCID: https://orcid.org/0000-0003-2025-0149)
- Anthony A. Hyman (ORCID: https://orcid.org/0000-0003-0851-704X)
- Wilfried Rossoll (ORCID: https://orcid.org/0000-0002-9622-541X)
- Aleksandra Sergeeva (ORCID: https://orcid.org/0000-0003-0117-9076)
- Nicolas Lux Fawzi (ORCID: https://orcid.org/0000-0001-5483-0577)
- Jik Nijssen (ORCID: https://orcid.org/0000-0003-0013-9750)
- Anh Ly
- Jeetain Mittal (ORCID: https://orcid.org/0000-0002-9725-6402)
- Patricia M. dos Passos
- Xiao Yan (ORCID: https://orcid.org/0000-0003-2635-8353)
- Jayakrishna Shenoy (ORCID: https://orcid.org/0000-0002-0360-645X)
- Leah George
Institutions
- Saint Louis University (ES)
- Brown University (US)
- Mayo Clinic in Florida (US)
- Center for Systems Biology Dresden (DE)
- Max Planck Institute of Molecular Cell Biology and Genetics (DE)
- Saint Louis University (US)
- Technische Universität Dresden (DE)
- Texas A&M University (US)
Publication Details
- Journal
- Cell
- Published
- 2025-05-23
- DOI
- https://doi.org/10.1016/j.cell.2025.04.039
- Citations
- 72
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 97.25