title: Dynactin is required for transport initiation from the distal axon.
abstract: Dynactin is a required cofactor for the minus-end-directed microtubule motor cytoplasmic dynein. Mutations within the highly conserved CAP-Gly domain of dynactin cause neurodegenerative disease. Here, we show that the CAP-Gly domain is necessary to enrich dynactin at the distal end of primary neurons. While the CAP-Gly domain is not required for sustained transport along the axon, we find that the distal accumulation facilitates the efficient initiation of retrograde vesicular transport from the neurite tip. Neurodegenerative disease mutations in the CAP-Gly domain prevent the distal enrichment of dynactin thereby inhibiting the initiation of retrograde transport. Thus, we propose a model in which distal dynactin is a key mediator in promoting the interaction among the microtubule, dynein motor, and cargo for the efficient initiation of transport. Mutations in the CAP-Gly domain disrupt the formation of the motor-cargo complex, highlighting the specific defects in axonal transport that may lead to neurodegeneration.
authors.affiliation: Department of Physiology, Perelman School of Medicine at the University of Pennsylvania, D400 Richards Building, 3700 Hamilton Walk, Philadelphia, PA 19104-6085, USA.
authors.forename: Armen J
authors.initials: AJ
authors.lastname: Moughamian
authors.forename: Erika L F
authors.initials: EL
authors.lastname: Holzbaur
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000502:physiology*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000072159:Dynactin Complex; D005727:Ganglia, Spinal / Q000166:cytology*; D005998:Glycine / Q000235:genetics; D047468:Immunoprecipitation; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D038761:Photobleaching; D017434:Protein Structure, Tertiary / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D044767:Ubiquitin-Protein Ligases; D052118:Lysosomal-Associated Membrane Protein 1; D000070584:Tripartite Motif Proteins
chemical_list: D004268:DNA-Binding Proteins; D000072159:Dynactin Complex; D005998:Glycine; D051907:Lysosomal Membrane Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D044767:Ubiquitin-Protein Ligases; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1; C489296:Trim27 protein, mouse; D000070584:Tripartite Motif Proteins