Tau-Induced Traffic Jams Reflect Organelles Accumulation at Points of Microtubule Polar Mismatching

It is currently accepted that tau overexpression leads to impaired organelle transport and thus to neuronal degeneration. Nevertheless, the underlying mechanisms that lead to impaired organelle transport are not entirely clear. Using cultured Aplysia neurons and online confocal imaging of human tau, microtubules (MTs), the plus-end tracking protein – end-binding protein 3, retrogradely and anterogradely transported organelles, we found that overexpression of tau generates the hallmarks of human tau pathogenesis. Nevertheless, in contrast to earlier reports, we found that the tau-induced impairment of organelle transportisbecauseofpolarreorientationofthe MTsalong the axon or their displacement to submembrane domains. ‘Traffic jams’ reflect the accumulation of organelles at points of MT polar discontinuations or polar mismatching rather than because of MT depolymerization. Our findings offer a new mechanistic explanation for earlier observations, which established that tau overexpression leads to impaired retrograde and anterograde organelle transport, while the MT skeleton appeared intact.