The role of Tau RNA complex formation in tau function and tauopathy disorders

Abstract

AbstractBackgroundPathological tau characterizes Alzheimer’s disease, FTLD‐tau, and other tauopathy disorders. Canonically, tau functions as a microtubule binding and stabilizing protein. The molecular mechanisms of tau mediated neurodegeneration remain incompletely understood. Recent studies from our group and others have shown that RNA binding proteins modulate the severity of tau pathology. Further, RNA has previously been demonstrated to drive tau aggregation in vitro. We hypothesize that tau itself may interact physically with RNA and/or RNA binding proteins, thereby altering tau MT related functions.MethodsWe employed biophysical and biochemical approaches to measure tau/RNA binding. To generate reagents for characterizing tau RNA complexes (TRCs) in human disease, we raised monoclonal antibodies as a tool to assess the formation of tau RNA complexes in human disease and animal models of disease.ResultsWe show tau binds single stranded RNA with high affinity but low sequence specificity. Tau seems to bind RNA homopolymers with higher affinity that with tubulin (α/β) dimers. Since poly(A) RNA is the most abundant RNA homopolymer in living cells and known poly(A) RNA binding proteins modulate tauopathy phenotypes, we investigated the ability of poly(A) RNA to form complexes with tau in vitro. Incubation of purified tau with poly(A) RNA promotes the formation of TRCs that appear as oligomeric tau species (N= ∼6‐20) by size exclusion chromatography. Tau binding to RNA inhibits tau microtubule polymerization activity. We generated a monoclonal antibody against purified TRCs and generated a conformation dependent monoclonal antibody called TRC35 that recognizes purified AD fibril tau over recombinant non‐fibrillar tau. Poly(A) binding proteins control TRC35+ accumulation in tau transgenic mice. We observe TRC35+ tau deposits in a wide variety of tauopathy disorders including Alzheimer’s disease, progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration, and Pick’s disease.ConclusionsTau binds RNA with high affinity. This tau RNA binding activity antagonizes tau action as microtubule stabilizing protein. Tau RNA binding stimulates tau oligomerization and the formation of a disease relevant conformational epitope. Poly(A) RNA binding proteins modulate TRC35+ deposits of pathological tau in model systems and Alzheimer’ s disease. TRC35+ lesions occur in diverse tauopathy disorders.