Tau: It’s Not What You Think

Tau is concentrated on the labile domain of the axonal microtubule, not the stable domain, which is contrary to the expectation of tau dogma. Contrary to tau dogma, when tau is depleted from neurons, the stable domain is no less stable, but the labile domain becomes shorter and more stable. When tau is depleted, MAP6, a genuine stabilizer of microtubules, is expressed more highly and binds to microtubules more avidly, providing an explanation for why the labile domain becomes more stable when tau is depleted. Competition between tau and MAP6 for binding to the microtubule is consistent with trending ideas on a process called ‘lattice gating’ by which the binding of one protein to the microtubule changes the lattice of the microtubule in a manner that makes it more or less amenable to the binding of another protein (or the same protein). The real role of tau in the regulation of microtubule stability in the axon is not to stabilize axonal microtubules, but rather to enable them to have long labile domains. Microtubule stabilization is likely to be achieved through signaling pathways that lead to tau phosphorylation, which leads to less tau affiliated with the labile domain of the microtubule and hence greater propensity for genuine stabilizers such as MAP6 to stabilize the microtubule. Microtubule-stabilizing drugs may not be a logical choice for treatment of tauopathies in human patients. More rational microtubule-based strategies for treating tauopathies would restore labile domains of axonal microtubules that are diminished as a result of tau detachment