TAU-INDUCED NEURODEGENERATION IS MEDIATED BY RNA BINDING PROTEINS

Abstract

The classic model of protein aggregation posits that aggregation of tau occurs as a random event. However, this model over-looks emerging the biology of RNA binding proteins (RBPs) and tau in producing RNA granules, which control RNA metabolism. RBPs readily aggregate through a tightly regulated mechanism involving liquid-liquid phase separation. Mutations in RBPs linked to neurological diseases increase the propensity of RBPs to aggregate, which can become irreversible with time. Recent cell culture studies show that the association of tau with RBPs promotes tau aggregation, while reducing T cell intracellular antigen 1 (TIA1), a core nucleating RBP, protects against tau-mediated toxicity. PS19 P301S tau mice were crossed with TIA1-/- to generate P301S tau x TIA1+/- and P301S tau x TIA1 -/- mice. Reducing TIA1 levels in vivo strongly protects against neurodegeneration and prolongs survival. PS19 x TIA1+/- mice exhibit a 26% increase in lifespan. The protection is associated with rescue of deficits in RNA metabolism, including a striking decrease in the number of cytoplasmic stress granules, a corresponding increase in nuclear TIA1, and rescue of dysfunctional RNA splicing. There is a correspondingly increased binding of tau to microtubules and microtubule stabilization. The mice show strongly improved neuronal/brain function, including protection against synaptic and neuronal loss, and improved spatial working memory. Remarkably, this protection occurs despite increased neurofibrillary tangles. Biochemical studies show that PS19 x TIA1+/- mice exhibit a striking reduction of soluble tau oligomers with a corresponding increase in levels of insoluble tau fibrils. These results point to dysfunction of RBPs and RNA metabolism as important factors contributing to tauopathy. We propose a new paradigm in which tau pathology is (in part) driven by the role of tau in the translational stress response, which is mediated by the interaction with RBPs and RNA granules. Excess aggregation of RBPs produces pathological stress granules, which promote tau aggregation and cause RNA metabolism dysfunction. Tau / RBPs interactions appear to enhance the accumulation of tau in an oligomeric state that is more toxic than fibrillar tau. These results suggest that RBPs could provide compelling targets for therapeutic development.