Cofactors at the core of tau prion behaviour

Introduction

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.

Prion Behavior

These assemblies can spread and recapitulate pathological phenotypes when injected in cells and animals. This is the hallmark that tau aggregates follow a prion behavior. To date, the factors guiding the formation or propagation of specific strains are unknown.

Knowledge Gap

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.

Hypothesis

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.

Objectives

To demonstrate this hypothesis, I will test that the tau-cofactor interactions:

1. Dictate the structure of tau aggregates.
2. Enable structure replication through seeding.
3. Dictate the neuropathology developed in cells and mice after inoculation of tau seeds.

Methodology

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.

Techniques

This proposal combines multiple methods including:

• EPR and NMR spectroscopy
• AFM-based nanospectroscopy
• Biochemistry
• Cell biology
• Animal histology

Impact

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.