Abstract

Tau is a microtubule (MT)-associated protein, which precisely localizes to the axon of a mature neuron. Although it has been widely used as an axonal marker, the mechanisms for its axonal localization have been elusive. This might be largely due to the lack of an experimental system, as exogenously expressed tau, such as GFP-tau, mis-localizes to the soma and dendrites. In this study, we found that the expression of endogenous tau and its axonal localization in cultured rat hippocampal neurons mainly occur during early neuronal development and are coupled. By mimicking this early expression, we demonstrate that exogenously expressed human tau can be properly localized to the axon, thereby providing the first experimental model to study the mechanisms of tau localization. Using this model, we obtained surprising findings that the axonal localization of tau did not require the MT-binding domain nor correlate with the MT-binding ability. Instead, we identified a transport mechanism mediated by the proline-rich region 2 (PRR2), which contains a number of important phosphorylation sites. Mimicking phosphorylation and dephosphorylation in PRR2 disrupts the axonal localization, suggesting that it is regulated by the phosphorylation state of PRR2. These results shed new lights on the mechanism for the axonal localization of tau and indicate a link between the hyperphosphorylation and mis-localization of tau observed in tauopathies.\n\nSignificance statementIn this paper, we present a first experimental system, in which expressed tau is properly localized to the axon, and which can therefore be used to study the mechanisms of tau localization and mis-localization. Using this system, we provide evidence that the microtubule binding domain of tau nor stable binding of tau to microtubules is not necessary for its axonal localization. Instead, we identified the proline-rich region and its phosphorylation-state dictate the localization of tau in neurons. These results provide a novel foundation to consider how axonal tau mis-localize to the soma and dendrites during early pathogenesis of Alzheimers disease.