title: Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration.
abstract: To test the hypothesis that inhibition of axonal transport is sufficient to cause motor neuron degeneration such as that observed in amyotrophic lateral sclerosis (ALS), we engineered a targeted disruption of the dynein-dynactin complex in postnatal motor neurons of transgenic mice. Dynamitin overexpression was found to disassemble dynactin, a required activator of cytoplasmic dynein, resulting in an inhibition of retrograde axonal transport. Mice overexpressing dynamitin demonstrate a late-onset progressive motor neuron degenerative disease characterized by decreased strength and endurance, motor neuron degeneration and loss, and denervation of muscle. Previous transgenic mouse models of ALS have shown abnormalities in microtubule-based axonal transport. In this report, we describe a mouse model that confirms the critical role of disrupted axonal transport in the pathogenesis of motor neuron degenerative disease.
authors.affiliation: Department of Physiology, School of Medicine, University of Pennsylvania, 3700 Hamilton Walk, Philadelphia 19104, USA.
authors.forename: Bernadette H
authors.initials: BH
authors.lastname: LaMonte
authors.forename: Karen E
authors.initials: KE
authors.lastname: Wallace
authors.forename: Beth A
authors.initials: BA
authors.lastname: Holloway
authors.forename: Spencer S
authors.initials: SS
authors.lastname: Shelly
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ascaño
authors.forename: Mariko
authors.initials: M
authors.lastname: Tokito
authors.forename: Thomas
authors.initials: T
authors.lastname: Van Winkle
authors.forename: David S
authors.initials: DS
authors.lastname: Howland
authors.forename: Erika L F
authors.initials: EL
authors.lastname: Holzbaur
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001370:Axonal Transport / Q000235:genetics*; D001369:Axons / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D016923:Cell Death / Q000235:genetics; D004195:Disease Models, Animal; D000072159:Dynactin Complex; D004398:Dyneins / Q000172:deficiency* / Q000235:genetics; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008869:Microtubule-Associated Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016900:Neurofilament Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013126:Spinal Nerve Roots / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D015854:Up-Regulation / Q000235:genetics
chemical_list: C000606365:Dctn2 protein, mouse; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D016900:Neurofilament Proteins; D004398:Dyneins