Mutations in tau protein promote aggregation by favoring extended conformations

Amyloid aggregation of the intrinsically disordered protein (IDP) tau is involved in several diseases, called tauopathies. Mutations in the gene encoding tau are responsible for a class of inherited tauopathies called frontotemporal dementia and parkinsonism linked to chromosome 17Q (FTDP-17). These mutations are thought to trigger FTDP-17 by favoring the formation of tau amyloid fibrils. This work aims at deciphering the mechanisms through which the diseases-associated single point mutations promote amyloid formation. We combined biochemical characterization and small angle X-ray scattering (SAXS) to study six different FTDP-17 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 radius of gyration. We show that mutations disfavor intramolecular protein interactions which in turn favor extended conformations and promote amyloid aggregation. This work proposes a new connection between the structural features of tau monomers and their propensity to aggregate, providing a novel assay to evaluate aggregation propensity of tau variants.