Periodic Reporting for period 1 - cofacTau (Cofactors at the core of tau prion behaviour)
Reporting period: 2022-09-01 to 2025-02-28
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.
This project intends to establish molecular rules that enable the formation and propagation of disease-specific tau strain. We are testing a 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. For that we study the pathological properties and the conformational evolution of tau aggregates in the presence of biologically-relevant cofactors possessing different physico-chemical properties. 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.
This project intends to establish molecular rules that enable the formation and propagation of disease-specific tau strain. We are testing a 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. For that we study the pathological properties and the conformational evolution of tau aggregates in the presence of biologically-relevant cofactors possessing different physico-chemical properties. 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.
We have investigated mechanisms through which the disease-associated single-point mutations promote amyloid formation. Some tauopathies can be inherited due to mutations in the gene encoding tau, which might favor the formation of tau amyloid fibrils. We combined biochemical and biophysical characterization, notably, small-angle X-ray scattering (SAXS), to study different tauopathy-derived mutations. We found that the mutations promote aggregation to different degrees and can modulate tau conformational ensembles, intermolecular interactions, and liquid–liquid phase separation propensity. In particular, we found a good correlation between the aggregation lag time of the mutants and their radii of gyration. We show that mutations disfavor intramolecular protein interactions, which in turn favor extended conformations and promote amyloid aggregation.
In addition, we have investigated how interactions between tau and biological membranes could lead to specific aggregation pathways. We have studied different types of lipids composing neuronal membranes in order to understand their relative contribution to tau aggregation, using different biophysical methods.
We also have characterized tau amyloid extracted from the brain of patient affected with different tauopathies. After specific extraction procedures, we are developing new spectroscopic methods to identify the structural cofactors present in tau aggregates from different tauopathies (see figure).
In addition, we have investigated how interactions between tau and biological membranes could lead to specific aggregation pathways. We have studied different types of lipids composing neuronal membranes in order to understand their relative contribution to tau aggregation, using different biophysical methods.
We also have characterized tau amyloid extracted from the brain of patient affected with different tauopathies. After specific extraction procedures, we are developing new spectroscopic methods to identify the structural cofactors present in tau aggregates from different tauopathies (see figure).
We have shown that the amyloid formation propensity of a disordered protein can be encoded in its structure at the monomer level. With this work, we have proposed a new connection between the structural features and propensity to aggregate, providing a novel assay to evaluate the aggregation propensity of IDPs.
We have also achieved a global model to explain how biological membranes could trigger the aggregation of the tau protein.
We have also achieved a global model to explain how biological membranes could trigger the aggregation of the tau protein.