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

• Published in: Current biology 2019-01, Vol.29 (2), p.268-282.e8
• Main Authors: Guedes-Dias, Pedro, Nirschl, Jeffrey J., Abreu, Nohely, Tokito, Mariko K., Janke, Carsten, Magiera, Maria M., Holzbaur, Erika L.F.
• Format: Article
• Language: English
• Subjects: Animals; axonal transport; dynein; Hippocampus - metabolism; KIF1A; kinesin; Kinesin - genetics; Kinesin - metabolism; microtubule dynamics; Microtubules - physiology; Neurons - metabolism; Rats; synaptic strength; synaptic vesicles; Synaptic Vesicles - physiology
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2018.11.065

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. [Display omitted] •Delivery of synaptic vesicle precursors occurs with high precision•Presynaptic sites are hotspots of dynamic GTP-rich microtubule plus ends•KIF1A binds more weakly to the GTP lattice, rapidly detaching from plus ends•A human KIF1A mutation perturbs lattice sensing and reduces synaptic strength Guedes-Dias et al. combine live and single-molecule imaging to show that local enrichment of microtubule GTP plus ends at en passant synapses specifies high-precision delivery of synaptic vesicles by KIF1A. Intrinsic weak binding of KIF1A to GTP-tubulin induces motor detachment at presynapses and regulates synaptic strength in hippocampal neurons.