Conformational Diversity of Wild-type Tau Fibrils Specified by Templated Conformation Change

Tauopathies are sporadic and genetic neurodegenerative diseases characterized by aggregation of the microtubule-associated protein Tau. Tau pathology occurs in over 20 phenotypically distinct neurodegenerative diseases, including Alzheimer disease and frontotemporal dementia. The molecular basis of this diversity among sporadic tauopathies is unknown, but distinct fibrillar wild-type (WT) Tau conformations could play a role. Using Fourier transform infrared spectroscopy, circular dichroism, and electron microscopy, we show that WT Tau fibrils and P301L/V337M Tau fibrils have distinct secondary structures, fragilities, and morphologies. Furthermore, P301L/V337M fibrillar seeds induce WT Tau monomer to form a novel fibrillar conformation, termed WT*, that is maintained over multiple seeding reactions. WT* has secondary structure, fragility, and morphology that are similar to P301L/V337M fibrils and distinct from WT fibrils. WT Tau is thus capable of conformational diversity that arises via templated conformation change, as has been described for amyloid β, β₂-microglobulin, and prion proteins.Tau filament deposition in Alzheimer disease, frontotemporal dementia, and other tauopathies correlates closely with cognitive dysfunction and cell death (1). About 10% of tauopathies are due to dominant mutations in the Tau gene. These diseases are collectively termed frontotemporal dementia with parkinsonism linked to chromosome 17, FTDP-17 (2–4). Most of the mutations occur in the microtubule-binding region of the Tau protein, which is thought to be both its functional (5) and pathogenic (6) “core.” Approximately 90% of tauopathies occur sporadically and involve only wild-type (WT)² Tau. Both familial and sporadic tauopathies vary by regional involvement, disease duration, age of onset, Tau isoform expression, and fibril morphology (7). It is unknown how the pathology of WT Tau might generate distinct disease phenotypes in sporadic tauopathies, and whether conformational diversity of the protein could potentially play a role in disease, as it does in prion disorders (8, 9).Mutations in the Tau gene can generate conformationally distinct Tau species. Structural differences between in vitro prepared WT, G272V, N279K, P301L, V337M, and ΔK280 Tau fibrils have been observed using Fourier transform infrared spectroscopy (FTIR) (10), and differential susceptibilities to protease cleavage in vitro have been described for WT and P301L Tau fibrils (11). Furthermore, Tau filaments extracted from diseased brain are often morphologically distinct, consisting of straight or paired helical filaments of various periodicities and widths (12). It is unknown whether WT Tau can assume self-propagating, structurally distinct fibrillar conformations, as has been described for amyloid β peptide (13), β₂-microglobulin (14), and the prion protein (15). In this study, we have used biochemical and biophysical methods to test the hypothesis that WT Tau fibrils exhibit conformational diversity that is maintained by templated conformation change.