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Cited by 153Microtubule and mitosis dynamicsNeuroscience and Neuropharmacology ResearchCellular transport and secretion

Kinesin-3 responds to local microtubule dynamics to target synaptic cargo delivery to the presynapse

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Guedes-Dias, Pedro, Nirschl, Jeffrey J., Abreu, Nohely, Tokito, Mariko K., Janke, Carsten, Magiera, Maria M., Holzbaur, Erika L.F.·2019·Current Biology
DOI 10.1016/j.cub.2018.11.065PMC PMC6342647
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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.

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  • Various microtubule-binding proteins have higher affinities for expanded or compacted lattices in vitro and can induce lattice expansion or compaction, respectively.

    “various microtubule-binding proteins have higher affinities for expanded or compacted lattices in vitro and can also induce lattice expansion or compaction, respectively (Ferro et al., 2022; Guedes-Dias et al., 2019; Peet et al., 2018; Shima et al., 2018; Watanabe et al., 2020; Zhang et al., 2017)”

    From StableMARK-decorated microtubules in cells have expanded lattices (2025) · cites this paper as Guedes-Dias et al., 2019

    The Results section reports that KIF1A binds more strongly to GDP-taxol-stabilized than to GMPCPP-stabilized microtubules in vitro. The Discussion describes GDP-like lattices as compacted and GTP-like lattices as expanded. Neither section shows that KIF1A, or another binding protein studied here, induces lattice compaction or expansion. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • KIF1A is sensitive to the nucleotide state of the microtubule lattice.

    “KIF1A, a neuronal cargo transporter critical for human health37–40 and sensitive to the nucleotide state of the microtubule lattice11.”

    From Microtubule lattice spacing governs cohesive envelope formation of tau family proteins (2022) · cites this paper as [11]

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Authors
Guedes-Dias, P., Nirschl, J. J., Abreu, N., Tokito, M. K., Janke, C., Magiera, M. M., & Holzbaur, E. L. F.
Affiliations
  • University of Pennsylvania (US)
  • Université Paris-Sud (FR)
Corresponding author
Holzbaur, Erika L.F.
ORCID
Venue
Current Biology
Publisher
Elsevier BV
Published
2019-01
Volume
29
Issue
2
Pages
268-282.e8
ISSN
0960-9822 (ISSN-L)
DOI
10.1016/j.cub.2018.11.065
PMC
PMC6342647
OpenAlex
W2907624470
Cited by
153
References
5
Citations by year
2026: 17 · 2025: 9 · 2024: 16 · 2023: 25 · 2022: 25 · 2021: 25 · 2020: 23 · 2019: 13
FWCI
11.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NIH (R01GM048661, R35 GM126950, F30NS092227)
  • ANR (ANR-10-LBX-0038, ANR-10-IDEX-0001-02 PSL)
  • Fondation pour la Recherche Medicale (DEQ20170336756)
  • Fondation Vaincre Alzheimer (FR-16055p)
  • NSF Science and Technology Center for Engineering MechanoBiology (CMMI-1548571)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
kinesin-3, KIF1A, microtubule dynamics, end-binding proteins, presynaptic neurotransmitter release, hippocampal neurons
MeSH terms
Animals, Hippocampus, Microtubules, Neurons, Synaptic Vesicles, Kinesins, Rats

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