Axon pathology in some neurodegenerative disorders involves mechanisms that are related to those occurring during Wallerian degeneration after axon injury. Wallerian degeneration has significant advantages as an experimental system in which to study these mechanisms. The use of this model has thus resulted in substantial recent progress that can be related back to disease mechanisms.
Although Wallerian degeneration differs from apoptosis, there is evidence that both involve distinct initiation and execution phases.
The slow Wallerian degeneration protein (WLDS) delays Wallerian degeneration tenfold through a gain-of-function mechanism. Loss-of-function mutations of newly identified modifiers Sarm1 and Phr1 (highwire in Drosophila melanogaster) have a comparable effect.
Other modifiers of Wallerian degeneration have been reported. Some have protective effects that are considerably weaker than WLDS. For others, the full extent of axon protection in vivo remains to be tested.
We propose that WLDS and/or nicotinamide mononucleotide adenylyltransferases (NMNATs), SARM1 and PHR1 are core components of the Wallerian degeneration pathway, whereas some of the other modifiers interact with the pathway less directly.
A series of studies indicate that WLDS delays axon loss, and sometimes symptoms, in many (although not all) disease models. Similar studies are needed to investigate the effects in disease models of mutating the more recently discovered modifiers of the Wallerian degeneration pathway.
Loss of the endogenous axonal protein NMNAT2 after injury is an excellent candidate for an event that could initiate Wallerian degeneration, although important questions remain. We suggest that various axonal stresses could also deplete axons of NMNAT2 in non-injury disorders.
Finally, in light of the novel modifiers of axonal degeneration, we describe intriguing possible links between Wallerian degeneration and wider biological mechanisms, and discuss a novel hypothesis for the evolution of Wallerian degeneration.
Axon degeneration is a prominent early feature of most neurodegenerative disorders and can also be induced directly by nerve injury in a process known as Wallerian degeneration. The discovery of genetic mutations that delay Wallerian degeneration has provided insight into mechanisms underlying axon degeneration in disease. Rapid Wallerian degeneration requires the pro-degenerative molecules SARM1 and PHR1. Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) is essential for axon growth and survival. Its loss from injured axons may activate Wallerian degeneration, whereas NMNAT overexpression rescues axons from degeneration. Here, we discuss the roles of these and other proposed regulators of Wallerian degeneration, new opportunities for understanding disease mechanisms and intriguing links between Wallerian degeneration, innate immunity, synaptic growth and cell death.
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This work was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) (M.P.C. and J.G.) and a Faculty of Medicine and Health Sciences, University of Nottingham, UK, non-clinical senior fellowship (L.C.).
The authors declare no competing financial interests.
- Axonal arbors
The terminal regions of axons exhibiting a variable degree of branching. Extreme cases such as nigrostriatal dopaminergic neurons have tens of thousands of branches.
- Nicotinamide mononucleotide adenylyltransferases
(NMNATs). Enzymes that catalyse the final step in NAD+ synthesis, on which all the NAD+ biosynthetic pathways converge.
- Chimeric gene
A gene formed by the fusion of two normal genes, which can occur as the result of genomic rearrangement such as an intra-chromosomal duplication or triplication, or an inter-chromosomal translocation. Expression of a fusion protein is one of several possible outcomes.
- Axonal transport
The bidirectional trafficking of molecules and organelles along axons. Long-range transport is mediated by the progression of kinesin (anterograde) and dynein (retrograde) motor proteins along microtubules.
- Innate immunity
A first line of defence against infection (and the only mechanism in invertebrates) comprising pathogen recognition by Toll-like receptors, cytokine secretion and inflammatory responses by natural killer cells, macrophages, neutrophils, and other such cells.
An active programme of cell death effected by caspases, a family of cysteine-dependent proteases, and regulated by BCL-2 family proteins.
(Mosaic analysis with a repressible cell marker). A Drosophila melanogaster genetics method to target homozygous mutations to a specific subset of cells on a heterozygous background, thereby avoiding complications such as embryonic lethality.
The post-translational, covalent attachment of palmitic acid, usually to cysteine residues as in nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2). Palmitoylated neuronal proteins include GAP43, PSD95 and huntingtin, and its roles include regulation of subcellular targeting and protein stability.
- Axon pruning
The developmentally programmed loss of axon branches, for example, during Drosophila melanogaster metamorphosis and refinement of retinotectal projections. Nerve growth factor withdrawal is used as a culture model of axon pruning, although how closely mechanisms are related is unclear.
An inhibitor of nicotinamide phosphoribosyltransferase (NAMPT) with an extended binding site at the interface between the two monomers. FK866 greatly lowers NAD+ concentration in many cell types, which is why it is used in clinical trials as an anti-cancer drug.
A protein that facilitates the folding or assembly of another protein to prevent misfolding and abnormal aggregation.
- Toll-like receptor
(TLR). A receptor for pathogen-associated molecular patterns (PAMPs) that signals through its Toll–interleukin-1 receptor (TIR) domain to activate inflammation or cell death. SARM1 is one of five intracellular adaptors for TLR signalling.
- Taxol-induced neuropathy
Peripheral neuropathy induced by cancer chemotherapy, involving thermal and mechanical allodynia and degeneration of sensory intra-epidermal nerve fibres. Other chemotherapy drugs such as vincristine, oxaliplatin and cisplatin give rise to similar neuropathies.
Axonal regions that are immediately adjacent to a node of Ranvier, surrounded by lateral loops of the myelin sheath, which form septate-like junctions with the thickened axolemma.
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Conforti, L., Gilley, J. & Coleman, M. Wallerian degeneration: an emerging axon death pathway linking injury and disease. Nat Rev Neurosci 15, 394–409 (2014). https://doi.org/10.1038/nrn3680
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