Tubulin polyglutamylation is a general traffic control mechanism in hippocampal neurons

Neurons are highly complex cells that heavily rely on intracellular transport to distribute a range of functionally essential cargoes within the cell. Posttranslational modifications of tubulin are emerging mechanisms to regulate microtubule functions, but their impact on neuronal transport is only marginally understood. Here we have systematically studied the impact of posttranslational polyglutamylation on axonal transport. In cultured hippocampal neurons, deletion of a single deglutamylase, CCP1, is sufficient to induce abnormal accumulation of polyglutamylation, i.e. hyperglutamylation. We next investigated how hyperglutamylation affects axonal transport of a range of functionally different neuronal cargoes: mitochondria, lysosomes, LAMP1 endosomes and BDNF vesicles. Strikingly, we found a reduced motility for all these cargoes, suggesting that polyglutamylation could act as a central regulator of cargo transport in neurons. This, together with the recent discovery that hyperglutamylation induces neurodegeneration, makes it likely that perturbed neuronal traffic could be one of the central molecular causes underlying this novel type of degeneration.