Tau monomer encodes strains
Tauopathies have diverse presentation, progression, and neuropathology. They are linked to tau prion strains, self-replicating assemblies of unique quaternary conformation. Strains can be propagated indefinitely in cultured cells, and induce unique patterns of transmissible neuropathology upon inoculation into mice. Aggregates from a single strain reproduce only that strain upon re-inoculation into cells or mice. DS9 and DS10 cell lines propagate distinct synthetic strains. Surprisingly, DS9 monomer inoculated into naive cells encoded an identical \"sub-strain,\" whereas DS10 monomer encoded multiple sub-strains. Sub-strains produced distinct pathology upon inoculation into a tauopathy mouse model (PS19). Brain-derived tau monomer from an Alzheimers brain encoded a single strain. Monomer from a corticobasal degeneration brain encoded three sub-strains in which monomer from each encoded all three upon re-inoculation into cells. Tau monomer thus adopts multiple, stable seed-competent conformations, each of which encodes a limited number of strains. This provides insights into the origins of distinct tauopathies.