Protein phosphatase 2A and tau: an orchestrated 'Pas de Deux'

The neuronal microtubule-associated protein tau serves a critical role in regulating axonal microtubule dynamics to support neuronal and synaptic functions. Furthermore, it contributes to glutamatergic regulation and synaptic plasticity. Emerging evidence also suggests that tau serves as a signaling scaffold. Tau function and subcellular localization are tightly regulated, in part, by the orchestrated interplay between phosphorylation and dephosphorylation events. Significantly, protein phosphatase type 2A (PP2A), encompassing the regulatory PPP2R2A (or B) subunit, is a major brain heterotrimeric enzyme and the primary tau Ser/Thr phosphatase in vivo. Herein, we closely examine how the intimate and compartmentalized interactions between PP2A and tau regulate tau phosphorylation and function, and play an essential role in neuronal homeostasis. We also review evidence supporting a strong link between deregulation of tau-PP2A functional interactions and the molecular underpinnings of various neurodegenerative diseases collectively called tauopathies. Lastly, we discuss the opportunities and associated challenges in more specifically targeting PP2A-tau interactions for drug development for tauopathies.