Project description
Identifying modulators of tau amyloid formation
Protein dysfunction is at the root of many pathologies. The Tau protein, mostly present in neurons, aggregate into amyloid fibrils, a hallmark of several diseases including Alzheimer’s. However, the mechanisms of tau amyloid formation remains unclear. The EU-funded cofacTau project will investigate tau aggregation in the presence of various biologically relevant co-factors. With advanced biochemical and biophysical techniques, the team will attempt to identify which factors modulate tau aggregation pathways and structural differentiation. Success will afford new insights into disease pathways and provide basis for new drug development strategies.
Objective
"Tau is an intrinsically disordered protein that regulates microtubule activity in neurons. Aggregation of tau into amyloid fibrils is diagnostic of several diseases, termed tauopathies, that include Alzheimer's disease. Distinct amyloid aggregate structures, so-called ""strains"", are involved in different tauopathies. These assemblies can spread and recapitulate pathological phenotypes when injected in cells and animals. This is the hallmark that tau aggregates follow a prion behaviour. To date, the factors guiding the formation or propagation of specific strains are unknown. Showcasing this crucial gap in knowledge is the fact that none of the brain-extracted tau amyloid structures has been reproduced in vitro. This project intends to establish a paradigm shift for the very definition of tau strain. I propose the novel hypothesis that the co-aggregation of tau with other biomolecules such as lipids or polyanions, so-called cofactors, is a defining property of tau prion strains. To demonstrate this hypothesis, I will test that the tau-cofactor interactions (i) dictate the structure of tau aggregates, (ii) enable structure replication through seeding and (iii) dictate the neuropathology developed in cells and mice after inoculation of tau seeds. My approach is to study the pathological properties and the conformational evolution of tau aggregates in the presence of biologically-relevant cofactors possessing different physico-chemical properties. By mapping the interactions between tau and cofactors, my goal is also to establish the canonical rules governing tau structural differentiation. This proposal combines multiple methods including EPR and NMR spectroscopy, AFM-based nanospectroscopy, biochemistry, cell biology and animal histology. The proposed paradigm shift would have a very high impact in the field of tauopathies, for example by enabling accurate structure-based drug discovery, revealing new drug targets and pinpointing key deleterious metabolic pathways.
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Fields of science
Not validated
Not validated
Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
75794 Paris
France