Condensation-dependent chaperone interactions of Tau and TDP-43 in the brain

• Applicant: Susanne Wegmann, Ph.D.
• Subject Area: Biochemistry ; Molecular and Cellular Neurology and Neuropathology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545039200

Alzheimer's disease and related neurodegenerative disorders are characterized by the pathological accumulation and aggregation of proteins in neurons. The two most abundant hallmark pathologies in age-related proteinopathies are aggregates of the neuronal microtubule-associated protein Tau and the TAR-DNA binding protein-43 (TDP-43). For both proteins the assembly into liquid-like condensates has been suggested as initial steps towards their pathological aggregation, but also as part of their normal biological function. How neurons maintain functional and prevent dysfunctional Tau and TDP-43 condensation is unclear. In the proposed work we will identify cellular chaperones that can (naturally) prevent the aggregation of Tau and TDP-43 in neuronal condensates. We will determine condensate specific interactions of Tau and TDP-43 with chaperones in living neurons and "artificial" condensates and determine their effects on liquid-aggregate transitions using advanced mass spectrometry and light microscopy techniques. The unbiased nature of the chosen approaches allows the identification of novel chaperones and of the complexity in the chaperone network preventing Tau and TDP-43 liquid-solid transitions, and therefore could pave the way for new therapeutic approaches in neurodegenerative diseases.

• DFG Programme: Research Units
• Subproject of: FOR 5872: Chaperone-mediated regulation of the emergence of disease-causing amyloids inside biomolecular condensates