Zn²⁺ decoration of microtubules arrests axonal transport and displaces tau, doublecortin, and MAP2C

Intracellular Zn²⁺ concentrations increase via depolarization-mediated influx or intracellular release, but the immediate effects of Zn²⁺ signals on neuron function are not fully understood. By simultaneous recording of cytosolic Zn²⁺ and organelle motility, we find that elevated Zn²⁺ (IC₅₀ ≈ 5–10 nM) reduces both lysosomal and mitochondrial motility in primary rat hippocampal neurons and HeLa cells. Using live-cell confocal microscopy and in vitro single-molecule TIRF imaging, we reveal that Zn²⁺ inhibits activity of motor proteins (kinesin and dynein) without disrupting their microtubule binding. Instead, Zn²⁺ directly binds to microtubules and selectively promotes detachment of tau, DCX, and MAP2C, but not MAP1B, MAP4, MAP7, MAP9, or p150glued. Bioinformatic predictions and structural modeling show that the Zn²⁺ binding sites on microtubules partially overlap with the microtubule binding sites of tau, DCX, dynein, and kinesin. Our results reveal that intraneuronal Zn²⁺ regulates axonal transport and microtubule-based processes by interacting with microtubules.