Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration.
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.
LaMonte
Bernadette H
BH
Department of Physiology, School of Medicine, University of Pennsylvania, 3700 Hamilton Walk, Philadelphia 19104, USA.
Wallace
Karen E
KE
Holloway
Beth A
BA
Shelly
Spencer S
SS
Ascaño
Jennifer
J
Tokito
Mariko
M
Van Winkle
Thomas
T
Howland
David S
DS
Holzbaur
Erika L F
EL
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
C000606365:Dctn2 protein, mouse; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D016900:Neurofilament Proteins; D004398:Dyneins