Disease associated mutations in tau encode for changes in aggregate structure conformation

Abstract

The accumulation of tau aggregates is associated with neurodegenerative diseases collectively known as tauopathies. Tau aggregates (fibrils) isolated from different tauopathies such as Alzheimer's Disease, corticobasal degeneration and progressive supranuclear palsy have distinct Cryo-EM structures with respect to their packed fibril cores. To understand the mechanisms by which tau can be sensitized to form distinct aggregate conformations, we created a panel of tau variants encoding for individual disease-associated missense mutations in full-length 0N4R tau (WT and 36 mutants). We developed a high-throughput protein purification platform for direct comparison of tau variants in biochemical assays. Structural analysis of the protease-resistant core of tau aggregates formed in vitro reveals that mutations can promote aggregate core packing distinct from that produced by WT tau. Comparing aggregate structure changes with aggregation kinetic parameters for tau mutants revealed no clear linkage between these two aggregation properties. We also found that tau mutation-dependent alterations of tau aggregate structure are not readily explained by current tau fibril structure data. This is the first study to show the broad potential of tau mutations to alter the packed core structures contained within aggregated tau and sheds new insights into the molecular mechanisms underlying the formation of tau aggregate structures that may drive their associated pathology in disease.