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FUNCTIONAL GENETIC CLASSIFICATION OF ASSEMBLY STRUCTURES IN TAUOPATHIES
Abstract
Abstract Body
Classification of tauopathies is based on immunohistochemical analyses of brain tissue. Conformations of tau assemblies, or seeds, in tauopathy brain lysate could provide a complementary metric for standard neuropathology. Biosensor cells that express tau repeat domain fused to fluorescent proteins will propagate self-replicating tau assemblies (strains) derived from patient material. Certain strains propagate indefinitely, and produce faithfully transmissible neuropathology upon inoculation into mice. Thus tau can be reasonably considered a mammalian prion. We hypothesize that, as for PrP prions, a “ground truth” of diagnosis in tauopathy could derive from underlying tau assembly conformation, rather than patterns of neuropathology. To build a relatively unbiased classification system, we have created a library of mutants with an alanine scan through the tau repeat domain. Using biosensor cells we have probed assembly of each alanine mutant onto existing stable strains, and onto transient intracellular assemblies induced by exposure to brain lysates. The relative incorporation of alanine mutants into intracellular aggregates is dictated by artificial “species barriers” they create. We thus derive a “fingerprint” of amino acids critical to build a given tau assembly. This unbiased, functional genetic dendrogram of tau prions predicts patterns of neuropathology following inoculation into a tauopathy mouse model. For human brain extracts, this method readily distinguishes different tauopathies. It also implicates amino acids outside the amyloid core defined by cryoEM as critical for stability. In ongoing work we are testing the validity of this structure-based classification scheme.