title: The p150(Glued) CAP-Gly domain regulates initiation of retrograde transport at synaptic termini.
abstract: p150(Glued) is the major subunit of dynactin, a complex that functions with dynein in minus-end-directed microtubule transport. Mutations within the p150(Glued) CAP-Gly microtubule-binding domain cause neurodegenerative diseases through an unclear mechanism. A p150(Glued) motor neuron degenerative disease-associated mutation introduced into the Drosophila Glued locus generates a partial loss-of-function allele (Gl(G38S)) with impaired neurotransmitter release and adult-onset locomotor dysfunction. Disruption of the p150(Glued) CAP-Gly domain in neurons causes a specific disruption of vesicle trafficking at terminal boutons (TBs), the distal-most ends of synapses. Gl(G38S) larvae accumulate endosomes along with dynein and kinesin motor proteins within swollen TBs, and genetic analyses show that kinesin and p150(Glued) function cooperatively at TBs to coordinate transport. Therefore, the p150(Glued) CAP-Gly domain regulates dynein-mediated retrograde transport at synaptic termini, and this function of dynactin is disrupted by a mutation that causes motor neuron disease.
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. tlloyd4@jhmi.edu
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Lloyd
authors.forename: James
authors.initials: J
authors.lastname: Machamer
authors.forename: Kathleen
authors.initials: K
authors.lastname: O'Hara
authors.forename: Ji Han
authors.initials: JH
authors.lastname: Kim
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Collins
authors.forename: Man Y
authors.initials: MY
authors.lastname: Wong
authors.forename: Brooke
authors.initials: B
authors.lastname: Sahin
authors.forename: Wendy
authors.initials: W
authors.lastname: Imlach
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Yang
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Levitan
authors.forename: Brian D
authors.initials: BD
authors.lastname: McCabe
authors.forename: Alex L
authors.initials: AL
authors.lastname: Kolodkin
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics; D000072159:Dynactin Complex; D004594:Electrophysiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D016547:Kinesins / Q000235:genetics / Q000378:metabolism; D007814:Larva; D008564:Membrane Potentials / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D016472:Motor Neuron Disease / Q000235:genetics; D009046:Motor Neurons / Q000502:physiology; D009154:Mutation / Q000235:genetics*; D009469:Neuromuscular Junction / Q000235:genetics / Q000502:physiology; D038761:Photobleaching; D017729:Presynaptic Terminals / Q000502:physiology*; D011485:Protein Binding / Q000235:genetics; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D009435:Synaptic Transmission / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D049452:Green Fluorescent Proteins; D016547:Kinesins