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Axonal Transport and Neurodegenerative Disease

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Intracellular Traffic and Neurodegenerative Disorders

Part of the book series: Research and Perspectives in Alzheimer's Disease ((ALZHEIMER))

Abstract

Active intracellular transport is required to maintain the extended cellular processes of neurons. Long-distance transport along the axon is mediated by molecular motor proteins moving along the microtubule cytoskeleton. Members of the kinesin family drive anterograde transport, from cell body to cell periphery. Traffic back to the cell body is driven by the microtubule motor cyto-plasmic dynein and its activator dynactin. Recent progress has provided insights into the mechanisms of motor protein function in axonal transport and the role of the microtubule-associated protein tau in regulating the spatial and temporal dynamics of microtubule motors. The dependence of the neuron on active axonal transport suggests that defects in the process might be causally linked to neurodegeneration. In particular, dynein-mediated transport is required to target old/misfolded/aggregated proteins for degradation, as well as to mediate the trophic factor signaling required to maintain a healthy neuron. The identification of disease-causing mutations in the retrograde motor complex has provided support for this hypothesis. Specifically, multiple mutations in the dynein heavy chain gene have been shown to cause neurodegeneration in the mouse, and a point mutation in the p150Glued subunit of dynactin has been identified as a cause of motor neuron degeneration in a human cohort. More generally, defects in axonal transport have been observed in a range of neurodegenerative diseases. We now propose a model in which both decreased efficiency of retrograde transport and alterations in retrograde signaling contribute to neurodegenerative disease.

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Authors and Affiliations

  1. Department of Physiology, University of Pennsylvania School of Medicine, D400 Richards Building, 3700 Hamilton Walk, Philadelphia, PA, 19104, USA

    Erika L. F. Holzbaur

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  1. Erika L. F. Holzbaur
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Editors and Affiliations

  1. Department of Laboratory Medicine and Pathobiology, University of Toronto, Tranz Neuroscience Bldg., Toronto, ON, M5S 3H2, Canada

    Peter H. St. George-Hyslop

  2. Department of Neurology, Standford University School of Medicine, Standford, CA, 94305-5316, USA

    William C. C. Mobley

  3. Fondation IPSEN Pour la Recherche Thérapeutique, 65, quai Georges Gorse, Boulogne Billancourt, 92650, Cedex - France

    Yves Christen

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Holzbaur, E.L.F. (2009). Axonal Transport and Neurodegenerative Disease. In: George-Hyslop, P.H.S., Mobley, W.C., Christen, Y. (eds) Intracellular Traffic and Neurodegenerative Disorders. Research and Perspectives in Alzheimer's Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-87941-1_3

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