Inhibition of dynein but not kinesin induces aberrant focal accumulation of neurofilaments within axonal neurites.
Studies from several laboratories indicate that the microtubule motors kinesin and dynein respectively participate in anterograde and retrograde axonal transport of neurofilaments. Inhibition of dynein function by transfection with a construct expressing dynamitin or intracellular delivery of anti-dynein antibodies accelerates anterograde transport, which has been interpreted to indicate that the opposing action of both motors mediates the normal distribution of neurofilaments along axons. Herein, we demonstrate that, while expression of relatively low levels of exogenous dynamitin indeed accelerated anterograde neurofilament transport along axonal neurites in culture, expression of progressively increasing levels of dynamitin induced focal accumulation of neurofilaments within axonal neurites and eventually caused neurite retraction. Inhibition of kinesin inhibited anterograde transport, but did not induce similar focal accumulations. These findings are consistent with studies indicating that perturbations in dynein activity can contribute to the aberrant accumulations of neurofilaments that accompany ALS/motor neuron disease.
Motil
Jennifer
J
Center for Cellular Neurobiology and Neurodegeneration Research, Department of Biological Sciences, University of Massachusetts Lowell, One University Avenue, Lowell, MA 01854, USA.
Dubey
Maya
M
Chan
Walter K-H
WK
Shea
Thomas B
TB
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects / Q000502:physiology*; D001369:Axons / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000378:metabolism* / Q000503:physiopathology; D000072159:Dynactin Complex; D004398:Dyneins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016547:Kinesins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016900:Neurofilament Proteins / Q000187:drug effects / Q000378:metabolism*
C000606365:Dctn2 protein, mouse; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D016900:Neurofilament Proteins; D004398:Dyneins; D016547:Kinesins