Zinc arrests axonal transport and displaces tau, doublecortin, and MAP2C from microtubules

Accurate delivery of cargo over long distances through axonal transport requires precise spatiotemporal regulation and relies on microtubule function. Here we discover that Zn 2+ influx via depolarization inhibits axonal transport. Zn 2+ -mediated inhibition is nonselective for cargo. Elevated Zn 2+ (IC 50 » 5-10 nM) reduces both lysosomal and mitochondrial motility in primary rat hippocampal neurons and HeLa cells. We further reveal that Zn 2+ directly binds to microtubules, inhibiting movement of motor proteins (kinesin and dynein) and promoting detachment of neuronal-specific MAPs (Tau, DCX, and MAP2C). We finally provide a detailed model of microtubule interactions with Tau, DCX, dynein, kinesin, and predict microtubule Zn 2+ binding sites. Our results reveal that Zn 2+ acts to inhibit the microtubule binding of tau, DCX, and MAP2C and can directly block the progression of motor proteins on microtubules. Intraneuronal Zn 2+ , therefore, is a critical signal for regulating axonal transport and microtubulebased processes.