Trends in Neurosciences
Volume 25, Issue 10, 1 October 2002, Pages 532-537
Journal home page for Trends in Neurosciences

Review
Axon pathology in neurological disease: a neglected therapeutic target

https://doi.org/10.1016/S0166-2236(02)02255-5Get rights and content

Abstract

In the C57BL/WldS mouse, a dominant mutation dramatically delays Wallerian degeneration in injury and disease, possibly by influencing multi-ubiquitination. Studies on this mouse show that axons and synapses degenerate by active and regulated mechanisms that are akin to apoptosis. Axon loss contributes to neurological symptoms in disorders as diverse as multiple sclerosis, stroke, traumatic brain and spinal cord injury, peripheral neuropathies and chronic neurodegenerative diseases, but it has been largely neglected in neuroprotective strategies. Defects in axonal transport, myelination or oxygenation could trigger such mechanisms of active axon degeneration. Understanding how these diverse insults might initiate an axon-degeneration process could lead to new therapeutic interventions.

Section snippets

Mechanisms of axon degeneration

Axon degeneration appears to be an auto-destructive process similar to apoptosis that can be triggered by diverse insults. The molecular mechanisms of axon degeneration are poorly understood in any context. The morphological features of Wallerian degeneration – the granular disintegration and beading of an axon distal to a site of injury [9] – are common to a spectrum of neurodegenerative disorders and can be triggered by neurotoxins [10] and by defects in myelin 11., 12., axonal transport [13]

The WldS mutation and gene

The WldS phenotype undergoes simple autosomal semi-dominant inheritance, indicating a mutation at a single locus [23]. The mutant gene has now been identified using positional cloning. Assays of Wallerian degeneration of injured sciatic nerves in an interspecific backcross mapped the mutation to distal mouse chromosome 4 [26], where an 85 kb tandem triplication was identified [27]. Within the triplication, a novel chimeric gene [28] encodes an in-frame fusion protein of the N-terminus of

The ubiquitin–proteasome pathway and axon degeneration

Because the WldS gene encodes a fusion protein, either parent protein could be responsible for the phenotype, or elements of both proteins might be required. However, the available evidence leans towards a mechanism involving the ubiquitin–proteasome pathway (UPP). First, the basal level of NAD is unaltered in the unlesioned WldS nervous system [7]. Second, transgenic expression of Nmnat fused to a shorter Ube4b sequence does not delay Wallerian degeneration (M.P. Coleman and V.H. Perry,

Protection from neurodegenerative disorders by WldS

WldS delays axon degeneration in a variety of disorders. Axons in the mutant are significantly less susceptible to vincrisitine toxicity than those of wild-type mice, suggesting a possible role in combating neurodegeneration induced by chemotherapy [8]. They are also more susceptible to ‘dying back’ in myelin-related peripheral neuropathy (in the P0-knockout mouse) and progressive motor neuron disease (in the pmn mouse), resulting in extended functional preservation (M. Samsam et al.,

Axon pathology in neurological disease

If we are able to manipulate the survival of axons in neurodegenerative disorders, what will be the applications? Axon loss is a major cause of symptoms, even in disorders where the primary defect lies elsewhere, because axons in the CNS are unable to regenerate and even in the PNS regeneration is not wholly successful. Axons are highly vulnerable: their unusual size, shape and high metabolic activity make them susceptible to injury, transport defects, ischaemia, oxidative damage and

Multiple sclerosis

Early studies of multiple sclerosis (MS) documented injured axons in plaques (reviewed in Ref. [43]), but axon injury has only recently emerged as a substantial, and perhaps the key, component of MS pathology. Textbooks describe MS as an inflammatory demyelinating disease of the CNS, in which T-cells and macrophages attack the myelin sheath, leading to regions of focal demyelination with relative sparing of axons [44]. However, loss of axons has been detected early in the disease by magnetic

Amyotrophic lateral sclerosis

There is considerable axonal loss in human ALS and in animal models of ALS and spinal muscular atrophy 14., 16., 52.. As in MS, this could mediate symptoms whatever the primary cause of disease. Motor neuron disease can be primarily an axonopathy, as in pmn, where specific protection of cell bodies fails to alleviate symptoms [4], but prevention of axonal loss does improve the phenotype 53., 54.. Mutations in neurofilament proteins, normally abundant components of the axonal cytoskeleton, cause

Axonal transport defects

Axons face a unique intracellular transport problem. Many proteins, such as those of the kinesin and dynein superfamilies (reviewed in Ref. [60]), mediate axonal transport and, not surprisingly, mutations in their genes results in axonal loss. Mutation of the gene encoding kinesin-related protein KIF1B can cause axon loss in Charcot–Marie–Tooth disease type 2A and an animal model [61], and overexpression of the dynein cofactor dynamitin slows retrograde axonal transport, causing late-onset

Acute disorders

Transected WldS axons are preserved for only several weeks, so delaying Wallerian degeneration might provide only limited insight into chronic disease. However, the implications for acute disorders could be far greater. Acute injuries to brain and spinal cord cause axon damage with clinical consequences. The extent of diffuse axon injury associated with head trauma, as revealed by APP immunocytochemistry [46], appears to be a major determinant of clinical outcome [71]. However, axon transection

Conclusion

Wallerian degeneration is not simply a passive atrophy of the axon. It is an active process, which is comparable to apoptosis and can be triggered in many ways. The nature of the WldS gene suggests a possible role for the UPP in the protective, and probably also the degenerative, process. WldS mice are a unique experimental tool with which to explore axon degeneration, investigate novel biochemical pathways and determine how axon degeneration contributes to neurodegenerative pathology and

Acknowledgements

We would like to thank Bogdan Beirowski (Dept of Anatomy, University of Cologne) for the images shown in Fig. 1 and T.A. Newman and D.J. Corkill (CNS Inflammation Group, University of Southampton) for the images shown in Fig. 2. The work of M.P.C. is funded by the Federal Ministry of Education and Research (FKZ: 01 KS 9502) and Center for Molecular Medicine (ZMMK), University of Cologne, Germany.

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