Abstract
Tauopathies have diverse presentation, progression, and neuropathology. They are linked to tau prion strains, self-replicating assemblies of unique quaternary conformation, whose origin is unknown. Strains can be propagated indefinitely in cultured cells, and induce unique patterns of transmissible neuropathology upon inoculation into mice. DS9 and DS10 cell lines propagate different synthetic strains that derive from recombinant tau. We previously observed that tau monomer adopts two conformational states: one that is inert (Mi) and one that is seed-competent (Ms) (Mirbaha et al., 2018). We have now found that Ms itself is comprised of multiple stable ensembles that encode unique strains. DS9 monomer inoculated into naive cells encoded only DS9, whereas DS10 monomer encoded multiple sub-strains. Sub-strains each induced distinct pathology upon inoculation into a tauopathy mouse model (PS19). Ms purified from an Alzeimer's disease brain encoded a single strain. Conversely, Ms from a corticobasal degeneration brain encoded three sub-strains, in which monomer from any one re-established all three upon inoculation into cells. Seed competent tau monomer thus adopts multiple, stable seed-competent conformations, each of which encodes a limited number of strains. This provides insight into the emergence of distinct tauopathies, and may improve diagnosis and therapy.
Highlights
Tauopathies are a diverse group of neurodegenerative diseases defined by the accumulation of tau amyloids in neurons and glia (Lee et al, 2001)
Experiments from our group and others subsequently indicated that tau transmits amyloid pathology into cultured cells and mouse brain that can move from cell to cell (Frost et al, 2009b; Clavaguera et al, 2009), and led to the idea that it is ‘prion-like.’
We found that tau forms strains that can be isolated and propagated from cell to cell in a stable line that expresses the repeat domain (RD) containing two disease-associated mutations (P301L/V337M) fused to yellow fluorescent protein (RD-YFP)
Summary
Tauopathies are a diverse group of neurodegenerative diseases defined by the accumulation of tau amyloids in neurons and glia (Lee et al, 2001). Biochemistry and Chemical Biology Neuroscience (PS19) that is based on expression of 1N4R human tau with a single disease-associated mutation (P301S) (Yoshiyama et al, 2007), created distinct neuropathological phenotypes These could be transmitted stably across multiple generations of mice, and back into the RD-YFP biosensor cells, where DS9 and DS10 strains displayed their original morphology (Sanders et al, 2014). An Ms protein might adopt multiple distinct conformations as an ensemble, each producing a single strain or subset of strains upon self-association in a multimeric assembly This would predict that the diversity of tau prion strains we have previously described (Sanders et al, 2014; Kaufman et al, 2016) could be linked back to a distinct set of conformers of tau monomer. We have addressed this question by studying strains propagated in HEK293T cells, DS9 and DS10, that were derived from recombinant fibrils, and others derived from AD and CBD brain
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