Research

The aggregation of the protein tau is involved in several neurodegenerative diseases, termed tauopathies, such as Alzheimer’s disease. In different tauopathies, tau aggregates adopt different structures, emphasizing a causal link between the nature of tau aggregates at a molecular level and the associated pathology. Our research aims at understanding the molecular rules governing aggregate structural differentiation and propagation. Using biophysical and biochemical techniques, we study the mechanisms of tau aggregation across different pathways. We have a particular interest in characterizing the interaction of tau protein with different cofactors such as GAG, nucleic acids and lipids.

Protein liquid-liquid phase separation (LLPS) is a ubiquitous phenomenon in which protein molecules partition into a highly concentrated phase surrounded by a low-concentration phase. The capacity to locally increase biomolecule concentrations is expected to heavily modulate protein functional and pathological activities. Tau has been shown to undergo LLPS, either on its own or in complex with a polyanionic cofactor (complex-LLPS), such as RNA and heparin. Although the link between tau LLPS and amyloid aggregation has been suggested, there are few descriptions of the mechanisms involved, let alone of the effect of LLPS on the aggregation pathway. We aim at understanding the driving forces of tau LLPS and its relationship to tau pathological activity, by characterizing the physico-chemical properties of the protein under LLPS.

Although we use multiple techniques such as vibrational spectroscopy, NMR and cryoEM, we have a particular interest in electron paramagnetic resonance spectroscopy (EPR). EPR allows to probe, site-specifically, both dynamical and structural properties of the protein. In particular, double electron-electron resonance spectroscopy (DEER) probe protein intramolecular distances with Angstrom-resolution. DEER provide an ideal and quick readout for the structural identity of tau in soluble, oligomer and fibril states. An instrumental platform is currently under development in Bordeaux.