FOR 5872:  Chaperone-mediated regulation of the emergence of disease-causing amyloids inside biomolecular condensates

• Subject Area: Biology ; Medicine ; Physics
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545039200

It is well established that many age-related neurodegenerative diseases are caused by protein misfolding and aggregation. However, we still have a very limited understanding of where and when the disease-causing protein conformers arise and what the molecular mechanisms are that could counteract the emergence of these conformers. Recent pioneering work has revealed a key role for biomolecular condensates in protein misfolding and disease emergence, but the molecular and structural details remain to be elucidated. In recent years, evidence has also emerged that molecular chaperones can regulate the assembly and properties of protein condensates, suggesting that they play a critical role as condensate quality control factors. However, the structural and molecular details of how chaperones regulate condensation-linked protein aggregation have so far remained elusive. This research unit brings together two research fields that have traditionally been strong in Germany but have so far operated largely independently: the field of protein folding and molecular chaperones and the field of biomolecular condensates. Our proposal constitutes a new approach to understand protein misfolding diseases through the lens of condensates. Our central aim is to investigate the role of chaperones in regulating condensate-forming proteins and how folding of these proteins is coupled to condensate assembly and the formation of disease-linked aggregates. We will study the molecular and structural details of how molecular chaperones regulate protein misfolding states and quantify the effects on condensation-linked aggregation, complemented by theoretical modelling of the interplay between condensation and aggregation. We envision that this research consortium will provide a much-needed understanding of the interplay between condensates, molecular chaperones, and protein misfolding diseases. Specific aims that the consortium is going to address: 1. Determine how different protein conformations and interactions promote the assembly of protein condensates and their conversion into amyloid fibrils. 2. Determine how molecular chaperones are recruited to condensates and how chaperone binding changes the conformational landscape and interactions of TDP-43, Tau and HTT. 3. Elucidate how chaperones regulate the assembly and disassembly of condensates as well as their physical properties and conversion into aggregates. 4. Elucidate how chaperones can regulate the emergence of cytotoxic oligomers and aggregates by altering condensate properties.

• DFG Programme: Research Units
• International Connection: Israel

Projects

• Chaperone-mediated regulation of liquid to solid phase transition of Huntingtin (HTT) (Applicants Kirstein, Janine ;  Liu, Fan )
• Chaperone remodelling of HTT exon-1 aberrant folding and association in condensation processes (Applicant Ebbinghaus, Simon )
• Chaperoning disease-associated tau protein by the JDP/Hsp70 system (Applicant Rosenzweig, Rina )
• Condensation-dependent chaperone interactions of Tau and TDP-43 in the brain (Applicant Wegmann, Ph.D., Susanne )
• Coordination Funds (Applicant Kirstein, Janine )
• Interactions between TDP-43 and compartment-specific quality control machinery (Applicant Hipp, Ph.D., Mark S. )
• Regulation of Tau phase separation and strain formation by the Hsp90 chaperone system (Applicant Zweckstetter, Markus )
• The role of molecular chaperones in shaping the assembly landscape of TDP-43 (Applicants Alberti, Simon ;  Mahamid, Ph.D., Julia )
• Theory for phase separation and aggregation regulated by chaperones (Applicant Weber, Christoph )

• Spokesperson: Professorin Dr. Janine Kirstein