O4‐12‐05: Interaction between microtubule‐associated protein tau and RNA binding proteins stimulates tau misfolding and stress granule formation

Microtubule associated protein tau (Tau) is predominantly expressed in axons, but the accumulation of misfolded/aggregated Tau in the somatic and dendritic compartments is a pathological hallmark of Alzheimer's disease (AD). The reason for this mislocalization and the role of dendritic tau is poorly understood. Identifying the biological signals that regulate this process could highlight novel therapeutic targets for AD. RNA binding proteins (RBPs) are a class of about 800 proteins that function in the nucleus to regulate mRNA maturation. RBPs also function in the cytoplasm where they regulate RNA translation, trafficking, sequestration and degradation; in neurons, these RNA functions occur mainly in the soma and dendrite. Increasing evidence links neurological disease processes to dysfunction of neuronal RBPs, RNA granules and stress granules (SGs). We have recently shown that RBPs, including TIA1, co-localize with neuropathology in brain tissue of subjects with Alzheimer's disease (AD) and fulfill the criteria of SGs. We hypothesized that Tau might function to regulate SG formation and the translational stress response. We used primary cultures of cortical neurons from tau knockout mice and TIA-1 knockout mice to examine the effects of tau on formation of stress granules containing TIA-1, and the effects of TIA-1 on tau misfolding. We examined the interactions of these proteins using immunocytochemistry, super-resolution imaging, immunoprecipitations, mass spectroscopy/proteomics, development of photo-convertible constructs and live cell imaging. We now report a novel function for tau in regulating dendritic RNA granules. Tau accelerates SG formation and is required for normal interactions of TIA1 with proteins linked to RNA metabolism. Loss of tau abrogates interactions of TIA1 with proteins linked to RNA metabolism, including ribosomal proteins and RNA binding proteins. TIA1 associated SGs also stimulate the pathophysiology of tau, increasing tau misfolding, slowing tau catabolism and stimulating neurodegeneration. The role of tau in translational biology identifies novel pharmacological interventions, such that preventing SG formation pharmacologically or via TIA1 knockout reduces tau granules and blocks tau-mediated neurodegeneration. Conversely, stimulating SG formation increases tau granules and promotes neurodegeneration. These results present novel functions for tau, and point to new routes for pharmacotherapy of tauopathies.