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Axonal transport deficits and neurodegenerative diseases

Nature Reviews Neuroscience volume 14, pages 161–176 (2013)Cite this article

Subjects

Key Points

  • Axonal transport delivers proteins, lipids, mRNA and mitochondria to the distal synapse and clears recycled or misfolded proteins. Such transport is involved in neurotransmission, neural trophic signalling and stress insult responses.

  • Cargoes are conveyed along the microtubule tracks in axons by motor proteins.

  • Disturbances in axonal transport are key pathological events that contribute to neurodegeneration in Alzheimer's disease, polyglutamine diseases, hereditary spastic paraplegia, Charcot–Marie–Tooth disease, amyotrophic lateral sclerosis and Parkinson's disease.

  • The identification of mutations in genes encoding motor proteins in patients with neurodegenerative diseases strongly supports the view that defective intracellular transport can directly trigger neuron degeneration.

  • Axonal transport deficits might arise through various mechanisms, including defects in cytoskeletal organization, impairment of motor protein attachment to microtubules, altered kinase activities, destabilization of motor–cargo binding and/or mitochondrial energetic breakdown.

  • Autophagy and RNA metabolism might also interfere with the efficiency of axonal transport.

Abstract

The intracellular transport of organelles along an axon is crucial for the maintenance and function of a neuron. Anterograde axonal transport has a role in supplying proteins and lipids to the distal synapse and mitochondria for local energy requirements, whereas retrograde transport is involved in the clearance of misfolded and aggregated proteins from the axon and the intracellular transport of distal trophic signals to the soma. Axonal transport can be affected by alterations to various components of the transport machinery. Here, we review the current state of knowledge about axonal transport defects that might contribute to the pathogenesis of particular neurodegenerative diseases.

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Figure 1: Components of the microtubule-based axonal transport system.
Figure 2: Axonal transport damage in Alzheimer's and Huntington's diseases.
Figure 3: Axonal transport damage in motor neuron diseases and peripheral axonopathies.

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Acknowledgements

The work carried out by J.-P.J. is supported by the Canadian Institutes of Health Research (CIHR), the ALS Society of Canada, the PrioNet Canada, the Fondation André-Delambre, the Muscular Dystrophy Association (USA) and the Robert Packard Center for ALS Research at Johns Hopkins. The work of S.M. is supported by the Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres maladies du motoneurone (ARSla), the Association Française contre les Myopathies (AFM) and the Fédération pour la Recherche sur le Cerveau (FRC).

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  1. Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, INSERM UMR_S975, CNRS UMR7225, Université Pierre et Marie Curie, Hôpital de la Pitié-Salpêtrière, 47–83 boulevard de l'Hôpital, Paris, 75013, France

    Stéphanie Millecamps

  2. Department of Psychiatry and Neuroscience, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Laval University, 2705 Boulevard Laurier, Quebec, Quebec City, G1V4G2, Canada

    Jean-Pierre Julien

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Neurofilaments

Neurofilaments are components of the neuronal cytoskeleton. They are intermediate filaments with a diameter of 10 nm and are composed of three subunits: the neurofilament light, medium and heavy chains.

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Millecamps, S., Julien, JP. Axonal transport deficits and neurodegenerative diseases. Nat Rev Neurosci 14, 161–176 (2013). https://doi.org/10.1038/nrn3380

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