Native tau structure is disrupted by disease-associated mutations that promote aggregation

Tauopathies are neurodegenerative diseases characterized by intracellular amyloid deposits of tau protein. Missense mutations in MAPT cause dominantly inherited tauopathies, but a biophysical mechanism driving its amyloid formation is poorly understood. Many disease-associated mutations localize within tau9s repeat domain at inter-repeat interfaces proximal to amyloidogenic sequences, such as 306 VQIVYK 311 . Using crosslink mass spectrometry, intramolecular FRET, in vitro peptide systems, simulations, and cell models, we provide evidence that the aggregation prone 306 VQIVYK 311 motif forms metastable compact structures with upstream sequences, which modulates aggregation propensity. Disease-associated mutations, isomerization of critical prolines, or alternative splicing are all sufficient to destabilize local structure and trigger spontaneous aggregation. These local structural rearrangements provide a biophysical framework supporting a model in which perturbations initiate early events in sporadic and genetic tau pathogenesis.