Axonal transport and neurological disease

Abstract

Axonal transport is the process whereby motor proteins actively navigate microtubules to deliver diverse cargoes, such as organelles, from one end of the axon to the other, and is widely regarded as essential for nerve development, function and survival. Mutations in genes encoding key components of the transport machinery, including motor proteins, motor adaptors and microtubules, have been discovered to cause neurological disease. Moreover, disruptions in axonal cargo trafficking have been extensively reported across a wide range of nervous system disorders. However, whether these impairments have a major causative role in, are contributing to or are simply a consequence of neuronal degeneration remains unclear. Therefore, the fundamental relevance of defective trafficking along axons to nerve dysfunction and pathology is often debated. In this article, we review the latest evidence emerging from human and in vivo studies on whether perturbations in axonal transport are indeed integral to the pathogenesis of neurological disease.

Key points

  • Mutations in various genes encoding components of the axonal transport machinery have been implicated in the pathogenesis of neurological diseases.

  • Defective axonal trafficking has been linked to many nervous system disorders, but whether it is a cause or consequence of neuropathology remains largely unresolved.

  • Intravital imaging of transport in axons of live mice provides some of the most compelling evidence that trafficking disturbances contribute to neuronal dysfunction.

  • Targeting of specific mechanisms of axonal transport might be a valid therapeutic strategy to treat neurological disease.

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Fig. 1: The axonal transport machinery.

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Acknowledgements

The authors’ work is supported by the Medical Research Council Career Development Award (MR/S006990/1 to J.N.S.), a Wellcome Trust Postdoctoral Fellowship for Clinicians (110043/Z/15/Z to A.M.R.), a Wellcome Trust Senior Investigator Award (107116/Z/15/Z to G.S.), the European Union’s Horizon 2020 Research and Innovation programme under grant agreement 739572 (to G.S.) and a UK Dementia Research Institute Foundation award (to G.S.).

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Glossary

Processivity

The ability of motor–cargo complexes to undergo axonal transport without dissociation from microtubules.

Coiled-coil domains

A structural motif composed of two or more α-helices wrapped around each other to form a supercoil. The coiled-coil domain of the cytoplasmic dynein–dynactin complex connects the ATPase domain with the microtubule-binding domain.

Run length

The total displacement covered by a motor–cargo complex without pausing.

Microtubule gliding assays

An experimental technique that is used to assess the activity of motor proteins, in which microtubules and ATP are applied to motors bound to glass coverslips.

N-Ethyl-N-nitrosourea

(ENU). A potent mutagen that is often used to generate mutant animal models.

Endosomes

Membranous organelles involved in intracellular transport, sorting and delivery of various substances, including growth factors, internalized from the cell exterior.

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Sleigh, J.N., Rossor, A.M., Fellows, A.D. et al. Axonal transport and neurological disease. Nat Rev Neurol 15, 691–703 (2019). https://doi.org/10.1038/s41582-019-0257-2

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