Axon degeneration mechanisms: commonality amid diversity

• Published in: Nature reviews. Neuroscience Vol. 6; no. 11; pp. 889 - 898
• Main Author: Coleman, Michael
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2005; Nature Publishing Group
• Subjects: Animal Genetics and Genomics; Animals; Axonal Transport; Axons - ultrastructure; Behavioral Sciences; Biological and medical sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Cell physiology; Central Nervous System - metabolism; Central Nervous System - pathology; Embryology: invertebrates and vertebrates. Teratology; Fundamental and applied biological sciences. Psychology; Humans; Hypotheses; Molecular and cellular biology; Morphology; Nerve Tissue Proteins - genetics; Neurobiology; Neurosciences; Organogenesis. Fetal development; Organogenesis. Physiological fonctions; Proteins; review-article; Secretion. Exocytosis; Sodium; Toxicity; Wallerian Degeneration - genetics; Wallerian Degeneration - metabolism; Wallerian Degeneration - pathology; Wallerian Degeneration - physiopathology; Mitochondria; Treatment; Calcium; Wallerian degeneration; Sodium; Dysfunction; Morphology; Biological transport; Axon; Strategy; Review; Convergence
• ISSN: 1471-003X; 1471-0048; 1471-0048; 1469-3178
• DOI: 10.1038/nrn1788

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 Wld S 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 Wld S 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. 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 ( Wld S ) 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.