title: Conformational diversity of wild-type Tau fibrils specified by templated conformation change.
abstract: 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 beta, beta2-microglobulin, and prion proteins.
authors.affiliation: Department of Neurology, University of California, San Francisco, California 94158, USA.
authors.forename: Bess
authors.initials: B
authors.lastname: Frost
authors.forename: Julian
authors.initials: J
authors.lastname: Ollesch
authors.forename: Holger
authors.initials: H
authors.lastname: Wille
authors.forename: Marc I
authors.initials: MI
authors.lastname: Diamond
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019943:Amino Acid Substitution; D002942:Circular Dichroism / Q000379:methods; D006801:Humans; D020125:Mutation, Missense; D020836:Protein Structure, Quaternary / Q000235:genetics; D017433:Protein Structure, Secondary / Q000235:genetics; D017550:Spectroscopy, Fourier Transform Infrared; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins