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.
Zn2+ decoration of microtubules arrests axonal transport and displaces tau, doublecortin, and MAP2C
Disclosures: The authors declare no competing interests exist.
- Award Id(s): R01NS110590,R01GM118492,R35GM139483,R35GM131744
Taylor F. Minckley, Lyndsie A. Salvagio, Dylan H. Fudge, Kristen Verhey, Steven M. Markus, Yan Qin; Zn2+ decoration of microtubules arrests axonal transport and displaces tau, doublecortin, and MAP2C. J Cell Biol 7 August 2023; 222 (8): e202208121. doi: https://doi.org/10.1083/jcb.202208121
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