Kinesin-3 Responds to Local Microtubule Dynamics to Target Synaptic Cargo Delivery to the Presynapse

Curr Biol. 2019 Jan 21;29(2):268-282.e8. doi: 10.1016/j.cub.2018.11.065. Epub 2019 Jan 3.

Abstract

Neurons in the CNS establish thousands of en passant synapses along their axons. Robust neurotransmission depends on the replenishment of synaptic components in a spatially precise manner. Using live-cell microscopy and single-molecule reconstitution assays, we find that the delivery of synaptic vesicle precursors (SVPs) to en passant synapses in hippocampal neurons is specified by an interplay between the kinesin-3 KIF1A motor and presynaptic microtubules. Presynaptic sites are hotspots of dynamic microtubules rich in GTP-tubulin. KIF1A binds more weakly to GTP-tubulin than GDP-tubulin and competes with end-binding (EB) proteins for binding to the microtubule plus end. A disease-causing mutation within KIF1A that reduces preferential binding to GDP- versus GTP-rich microtubules disrupts SVP delivery and reduces presynaptic release upon neuronal stimulation. Thus, the localized enrichment of dynamic microtubules along the axon specifies a localized unloading zone that ensures the accurate delivery of SVPs, controlling presynaptic strength in hippocampal neurons.

Keywords: KIF1A; axonal transport; dynein; kinesin; microtubule dynamics; synaptic strength; synaptic vesicles.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Hippocampus / metabolism*
  • Kinesin / genetics*
  • Kinesin / metabolism
  • Microtubules / physiology*
  • Neurons / metabolism*
  • Rats
  • Synaptic Vesicles / physiology*

Substances

  • Kif1a protein, rat
  • Kinesin