Project Details
Projekt
The role of molecular chaperones in shaping the assembly landscape of TDP-43
Applicants
Professor Dr. Simon Alberti; Julia Mahamid, Ph.D.
Subject Area
Biochemistry
Biophysics
Cell Biology
Biophysics
Cell Biology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 545039200
Cytosolic aggregation of the nuclear protein TDP-43 is implicated in numerous neurodegenerative diseases. We recently demonstrated that TDP-43 aggregation requires two events: concentration within stress granule condensates and oxidative stress. Together, these events induce intra-condensate demixing of TDP-43, forming a dynamic TDP-43-enriched phase that promotes the formation of aggregates with hallmarks of pathological TDP-43 inclusions, such as their conjugation with ubiquitin and association with molecular chaperones. Mechanistically, TDP-43 de-mixing requires unfolding of its RNA Recognition Motif (RRM) domains and interactions mediated by the hydrophobic C-terminal domain, but the molecular details and order of events are not well understood. Here, we will focus on elucidating the mechanisms of pathological TDP-43 aggrega-tion inside condensates and the role of molecular chaperones in mitigating this process. Specifically, we aim to: (1) Study the conformational changes underlying TDP-43 assembly into con-densates and aggregates, (2) Analyze how chaperones modulate TDP-43 misfolding and assembly in vitro, (3) Dissect the role of condensates and chaperones in regulating TDP-43 misfolding and aggregation in living cells. (4) Visualize TDP-43 aggregation and chaperone action inside condensates in living cells. For this purpose, we combine the expertise of two teams. The Alberti team is at the forefront of research on the role of aberrant condensates in disease. The Mahamid team is a world-leading expert in Cryo-Electron Microscopy and Tomography of condensates in vitro and in situ. The two teams will join forces to dissect the role of biomolecular condensates in TDP-43 aggregation and uncover how chaperones modulate TDP-43 misfolding and aggregation, thus providing a foundation for chaperone-based therapies of neurodegenerative diseases.
DFG Programme
Research Units
