Chaperoning disease-associated tau protein by the JDP/Hsp70 system

• Applicant: Professorin Dr. Rina Rosenzweig
• Subject Area: Biochemistry
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545039200

Tau is essential to microtubule self-assembly and stability, but aberrant post-translational modifications (PTMs), such as hyperphosphorylation and acetylation, reduce the affinity of this protein for microtubules, leading to its dissociation and subsequent aggregation into amyloid fibrils. Such pathological aggregation of tau disrupts neuronal functions and is a hallmark of multiple tauopathies, including Alzheimer’s disease. Recent findings indicate that tau, as an intrinsically disordered protein (IDP), can also form liquid-like condensates, with liquid-to-solid phase transitions implicated as early steps in pathological aggregation. Molecular chaperones, particularly the Hsp40 (J-domain protein, JDP) family, play critical roles in modulating tau interaction with microtubules, phase separation (PS), degradation, and pathological aggregation. However, the mechanisms by which JDP chaperones selectively interact with tau and regulate its conformational states remain poorly understood. Further complicating this issue is the fact that the known chaperone binding sites on tau lie within the hydrophobic microtubule-binding repeat regions (MTBRs), which, while accessible in the monomeric tau, may become inaccessible during phase separation or fibril formation. We hypothesize that certain JDPs can regulate the conformational landscape of tau by targeting alternative binding sites outside the MTBRs, such as the N- and C-terminal regions, which remain exposed during phase separation and aggregation. Here we aim to elucidate these JDP-tau interactions and their regulatory impact on the functional and pathological states of tau, using state-of-the-art NMR spectroscopy, combined with biochemical and biophysical assays. Additionally, we will investigate how these interactions vary across the six major tau isoforms expressed in the brain - some of which lack key chaperone-binding regions - and how these interactions are influenced by PTMs and disease-associated mutations. Combined, our results will not only provide novel insights into the ability of JDP chaperones to recognize the diverse states of tau, but could lay the groundwork for developing targeted therapeutic strategies to modulate these interactions, potentially preventing or even reversing the devastating effects of the pathological aggregation of tau.

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