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  • Review Article
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Axon degeneration mechanisms: commonality amid diversity

Nature Reviews Neuroscience volume 6, pages 889–898 (2005)Cite this article

Key Points

  • The diversity of triggers for axon degeneration and apparent differences in the axonal responses suggest that diverse mechanisms of axon degeneration might operate in different disorders.

  • The genetic, immunochemical and pharmacological tools needed to test this hypothesis have only recently become available. New longitudinal and real-time imaging tools are also changing the way we look at axon pathology.

  • The slow Wallerian degeneration gene WldS delays injury-induced Wallerian degeneration by tenfold. The same gene delays axon degeneration in genetic and toxic disorders in which axonal transport is impaired, which indicates that similar mechanisms underlie axon degeneration in these widely differing circumstances.

  • Wallerian degeneration seems to be a proactive and closely regulated mechanism, similar in principle to apoptosis but distinct in molecular terms. By understanding how it is regulated we might be able to manipulate Wallerian degeneration in both experimental and clinical settings.

  • The WldS gene has been identified, but its mode of action is currently the subject of controversy. The protein might act through its inherent NAD+ synthesis activity and/or by interfering with the ubiquitin–proteasome system, and it may act in the nucleus, but a direct axonal role has also been proposed.

  • Immunocytochemical detection of amyloid precursor protein and imaging of axonal spheroids suggest that impairment of axonal transport is a widespread and early event in many neurodegenerative disorders of the CNS.

  • Degenerating axons can now be imaged more effectively using endogenous fluorescent labels that are expressed in neuronal subsets of transgenic mice, such as the YFP-H and GFP-S lines. This is transforming our understanding of the spatiotemporal events that occur during axon degeneration, and some surprising similarities are emerging between CNS and PNS events, and between axonal spheroids in various CNS disorders.

  • Pharmacological blockade of sodium and calcium influx can prolong the survival of axons damaged by inflammatory, anoxic and traumatic injuries, which further supports an underlying mechanistic similarity.

  • Taken together, the evidence suggests a convergent pathway of axon degeneration. The principal convergence points are poor axonal transport, mitochondrial dysfunction and an increase in intra-axonal calcium.

  • The convergent nature of axon degeneration offers important opportunities to combine knowledge of mechanisms and therapeutic strategies across different disorders.

Abstract

A wide range of insults can trigger axon degeneration, and axons respond with diverse morphology, topology and speed. However, recent genetic, immunochemical, morphological and pharmacological investigations point to convergent degeneration mechanisms. The principal convergence points — poor axonal transport, mitochondrial dysfunction and an increase in intra-axonal calcium — have been identified by rescuing axons with the slow Wallerian degeneration gene (WldS) and studies with blockers of sodium or calcium influx. By understanding how the pathways fit together, we can combine our knowledge of mechanisms, and potentially also treatment strategies, from different axonal disorders.

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Figure 1: Dying back and focal lesion models of axon degeneration.
Figure 2: Axonal varicosities, spheroids and end bulbs.
Figure 3: Convergent pathways of axon degeneration.

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Acknowledgements

This work was funded by the Biotechnology and Biological Sciences Research Council (BBSRC). The author thanks B. Beirowski, L. Conforti and R. Adalbert for helpful discussion, and R. Ribchester and T. Gillingwater for helpful discussion and permission to cite unpublished data.

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Authors and Affiliations

  1. The Babraham Institute, Babraham, CB2 4AT, Cambridge, UK

    Michael Coleman

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DATABASES

Entrez Gene

BAK

BAX

BCL2

CASPR

CNP1

ERBB2

ERK1

NMNAT1

SIRT1

SOD1

UBE4B

UCHL1

VCP

OMIM

Alzheimer's disease

amyotrophic lateral sclerosis

Creutzfeldt–Jakob disease

Parkinson's disease

FURTHER INFORMATION

Coleman's laboratory

Glossary

WALLERIAN DEGENERATION

The degeneration of an axon distal to a site of injury, which begins to occur about 1.5 days after a lesion.

AMYLOID PRECURSOR PROTEIN

(APP). A membrane glycoprotein component of fast axonal transport, from which Aβ is cleaved by proteloytic processing.

SODIUM–CALCIUM EXCHANGER

The protein that couples sodium influx to calcium efflux. This may function in reverse if intracellular sodium concentrations increase.

CHARCOT–MARIE–TOOTH DISEASE

Hereditary neuronopathy that involves both sensory and motor axons. Can originate from defects in myelin (type I) or axons (type II).

TAXOL

A microtubule-stabilizing drug used in cancer chemotherapy. Because of its action on microtubules, side effects of Taxol include peripheral neuropathy. Taxol dosage must be limited for this reason.

AXONAL SPHEROID

Focal swelling of an axon, usually in the CNS, to many times its usual diameter, typically swelling to 10–50 μm. Spheroids are often filled with disorganized cytoskeleton and organelles, and many stain positively for APP.

GRACILE TRACT

An axon tract in the dorsal spinal cord that carries proprioceptive axon branches from the dorsal root ganglion to the medulla oblongata.

VARICOSITIES

Minor swellings of axons, typically of less than 10 μm.

AXONAL DYSTROPHY

Generic term for misshapen axons in pathology that encompasses both larger spheroids and smaller varicosities.

ACUTE AXON DEGENERATION

(AAD). Rapid retraction of proximal and distal axon stumps from a site of spinal cord transection, which occurs ∼30 min after the lesion.

POSITIONAL CLONING

Identification of a gene on the basis of its chromosomal location.

SILENT INFORMATION REGULATOR

(Also known as sirtuin). NAD-dependent deacetylase that is involved in gene silencing and can influence longevity in some species.

VALOSIN-CONTAINING PROTEIN

An essential component of the ubiquitin–proteasome system that transfers multi-ubiquitinated proteins to the proteasome in endoplasmic reticulum, and has other known and unknown cellular roles.

END BULBS

Large swellings of up to 50 μm in diameter that develop terminally on both proximal and distal axon stumps after transection.

INSERTIONAL SILENCING

Silencing of transgene expression by genomic elements at the site of integration.

PARANODE

Region adjacent to nodes of Ranvier, where a series of cytoplasmic loops form septate-like junctions with the axon, acting as a diffusion barrier between node and internode.

AMYLOID PLAQUES

Sites of Aβ accumulation and dystrophic neurites in the brains of mouse models and patients with Alzheimer's disease.

Aβ IMMUNOTHERAPY

Amyloid clearance from the brains of mouse models of Alzheimer's disease using antibodies to Aβ.

CALPAINS

Ubiquitous calcium-dependent cysteine proteases that are strongly implicated in the later stages of Wallerian degeneration.

BEPRIDIL

A broad-range calcium channel blocker with a strong inhibitory effect on sodium–calcium exchange and on sodium channels.

PHENYTOIN

A drug that blocks sodium channels and inhibits persistent sodium currents, commonly used as an anticonvulsant.

FLECAINIDE

A sodium channel blocker used extensively as an anti-arrhythmic drug to correct irregular heartbeats.

SCHMIDT–LANTERMAN INCISURES

Regions of non-compacted myelin in peripheral nerves that allow communication between the Schwann cell cytoplasm adjacent to the axon and that on the external surface of the myelin sheath.

MITOCHONDRIAL UNCOUPLING

Prevents the oxidative phosphorylation of ADP to ATP in mitochondria without affecting electron transport, so that respiration no longer yields energy in the form of ATP.

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Coleman, M. Axon degeneration mechanisms: commonality amid diversity. Nat Rev Neurosci 6, 889–898 (2005). https://doi.org/10.1038/nrn1788

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