Wallerian degeneration: an emerging axon death pathway linking injury and disease

Key Points

  • 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.

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Systems for studying axon degeneration.
Figure 2: Structure–activity relationships of WLDS and SARM1.
Figure 3: NAD+ metabolism and compartmentalization in neurons.
Figure 4: An emerging molecular pathway of Wallerian and WLDS-sensitive axon degeneration.

References

  1. 1

    Samuel, M. A., Zhang, Y., Meister, M. & Sanes, J. R. Age-related alterations in neurons of the mouse retina. J. Neurosci. 31, 16033–16044 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Beirowski, B. et al. The progressive nature of Wallerian degeneration in wild-type and slow Wallerian degeneration (WldS) nerves. BMC Neurosci. 6, 6 (2005).

    PubMed  PubMed Central  Google Scholar 

  3. 3

    Mack, T. G. et al. Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene. Nature Neurosci. 4, 1199–1206 (2001). This study identifies the UBE4B–NMNAT1 fusion protein as WLDS, the causal factor delaying axon degeneration for up to 2 weeks after axon injury, by reproducing the phenotype in transgenic mice. It also reports that this protein is particularly abundant in neuronal nuclei.

    CAS  PubMed  Google Scholar 

  4. 4

    Osterloh, J. M. et al. dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science 337, 481–484 (2012). This study uses D. melanogaster genetics to identify a novel pro-axon death protein SARM1. Deletions of dSarm1 in D. melanogaster or its mouse orthologue remarkably delay injury-induced axon degeneration tenfold both in vivo and in primary neuronal culture, comparable to the effect of WLDS.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Babetto, E., Beirowski, B., Russler, E. V., Milbrandt, J. & Diantonio, A. The Phr1 ubiquitin ligase promotes injury-induced axon self-destruction. Cell Rep. 3, 1422–1429 (2013). This study shows that the mammalian ubiquitin ligase PHR1 is at least partly responsible for the turnover of NMNAT2. Its conditional deletion delays Wallerian degeneration both in vivo with an effect approaching that of WLDS, and to a lesser extent in primary neuronal cultures.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Sasaki, Y., Vohra, B., Baloh, R. & Milbrandt, J. Transgenic mice expressing the Nmnat1 protein manifest robust delay in axonal degeneration in vivo. J. Neurosci. 29, 6526–6534 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Milde, S., Fox, A. N., Freeman, M. R. & Coleman, M. P. Deletions within its subcellular targeting domain enhance the axon protective capacity of Nmnat2 in vivo. Sci. Rep. 3, 2567 (2013).

    PubMed  PubMed Central  Google Scholar 

  8. 8

    Yahata, N., Yuasa, S. & Araki, T. Nicotinamide mononucleotide adenylyltransferase expression in mitochondrial matrix delays Wallerian degeneration. J. Neurosci. 29, 6276–6284 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Babetto, E. et al. Targeting NMNAT1 to axons and synapses transforms its neuroprotective potency in vivo. J. Neurosci. 30, 13291–13304 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Gilley, J. & Coleman, M. P. Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons. PLoS Biol. 8, e1000300 (2010). This study shows that NMNAT2 is an endogenous, labile axonal protein that undergoes fast axonal transport and is required for axon survival in primary neuronal cultures. It shows that WLDS and other NMNATs are far more stable proteins and proposes that this underlies their ability to preserve injured axons for extended periods, the 'NMNAT2 depletion hypothesis'.

    PubMed  PubMed Central  Google Scholar 

  11. 11

    Gilley, J., Adalbert, R., Yu, G. & Coleman, M. P. Rescue of peripheral and CNS axon defects in mice lacking NMNAT2. J. Neurosci. 33, 13410–13424 (2013). This study demonstrates that severe depletion of NMNAT2 in mice causes defects in axon growth both in peripheral nerves and in CNS, leading to perinatal lethality. WLDS rescues these defects and abolishes the lethality caused by NMNAT2 deprivation.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Hicks, A. N. et al. Nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) regulates axon integrity in the mouse embryo. PLoS ONE 7, e47869 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    MacDonald, J. M. et al. The Drosophila cell corpse engulfment receptor Draper mediates glial clearance of severed axons. Neuron 50, 869–881 (2006).

    CAS  PubMed  Google Scholar 

  14. 14

    Hoopfer, E. D. et al. Wlds protection distinguishes axon degeneration following injury from naturally occurring developmental pruning. Neuron 50, 883–895 (2006).

    CAS  PubMed  Google Scholar 

  15. 15

    Xiong, X. et al. The Highwire ubiquitin ligase promotes axonal degeneration by tuning levels of Nmnat protein. PLoS Biol. 10, e1001440 (2012). This study demonstrates that the D. melanogaster ubiquitin ligase Highwire is involved in the proteasomal degradation of dNmnat, or of ectopically expressed mammalian NMNAT2, and that its loss of function delays axon degeneration. This is consistent with the notion that degradation of the axonal NMNAT pool is one event initiating injury-induced axon death.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Coleman, M. P. The challenges of axon survival: introduction to the special issue on axonal degeneration. Exp. Neurol. 246, 1–5 (2013).

    CAS  PubMed  Google Scholar 

  17. 17

    Wang, M. S., Davis, A. A., Culver, D. G. & Glass, J. D. WldS mice are resistant to paclitaxel (taxol) neuropathy. Ann. Neurol. 52, 442–447 (2002).

    PubMed  Google Scholar 

  18. 18

    Sajadi, A., Schneider, B. L. & Aebischer, P. Wlds-mediated protection of dopaminergic fibers in an animal model of Parkinson disease. Curr. Biol. 14, 326–330 (2004).

    CAS  PubMed  Google Scholar 

  19. 19

    Hasbani, D. M. & O'Malley, K. L. WldS mice are protected against the Parkinsonian mimetic MPTP. Exp. Neurol. 202, 93–99 (2006).

    CAS  PubMed  Google Scholar 

  20. 20

    Ferri, A., Sanes, J. R., Coleman, M. P., Cunningham, J. M. & Kato, A. C. Inhibiting axon degeneration and synapse loss attenuates apoptosis and disease progression in a mouse model of motoneuron disease. Curr. Biol. 13, 669–673 (2003). This was the first of many studies to show the ability of WLDS to modify disease onset and progression in vivo . The authors use a model of motor neuron disease, characterized by loss of tubulin-specific chaperone E (TBCE), to show that introducing WLDS in this mouse model delays symptom onset and significantly extends lifespan.

    CAS  PubMed  Google Scholar 

  21. 21

    Coleman, M. Axon degeneration mechanisms: commonality amid diversity. Nature Rev. Neurosci. 6, 889–898 (2005).

    CAS  Google Scholar 

  22. 22

    Vande Velde, C., Garcia, M. L., Yin, X., Trapp, B. D. & Cleveland, D. W. The neuroprotective factor Wlds does not attenuate mutant SOD1-mediated motor neuron disease. Neuromolecular Med. 5, 193–203 (2004).

    CAS  PubMed  Google Scholar 

  23. 23

    Waller, A. Experiments on the section of the glossopharyngeal and hypoglossal nerves of the frog, and observations of the alterations produced thereby in the structure of their primitive fibres. Phil. Trans. R. Soc. Lond. 140, 423–429 (1850).

    Google Scholar 

  24. 24

    Lunn, E. R., Perry, V. H., Brown, M. C., Rosen, H. & Gordon, S. Absence of Wallerian degeneration does not hinder regeneration in peripheral nerve. Eur. J. Neurosci. 1, 27–33 (1989).

    CAS  PubMed  Google Scholar 

  25. 25

    Howell, G. R. et al. Axons of retinal ganglion cells are insulted in the optic nerve early in DBA/2J glaucoma. J. Cell Biol. 179, 1523–1537 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Beirowski, B., Babetto, E., Coleman, M. P. & Martin, K. R. The WldS gene delays axonal but not somatic degeneration in a rat glaucoma model. Eur. J. Neurosci. 28, 1166–1179 (2008).

    PubMed  Google Scholar 

  27. 27

    Deckwerth, T. L. & Johnson, E. M. Neurites can remain viable after destruction of the neuronal soma by programmed cell death (apoptosis). Dev. Biol. 165, 63–72 (1994).

    CAS  PubMed  Google Scholar 

  28. 28

    Finn, J. T. et al. Evidence that Wallerian degeneration and localized axon degeneration induced by local neurotrophin deprivation do not involve caspases. J. Neurosci. 20, 1333–1341 (2000).

    CAS  PubMed  Google Scholar 

  29. 29

    Adalbert, R., Nógrádi, A., Szabó, A. & Coleman, M. P. The slow Wallerian degeneration gene in vivo protects motor axons but not their cell bodies after avulsion and neonatal axotomy. Eur. J. Neurosci. 24, 2163–2168 (2006).

    PubMed  Google Scholar 

  30. 30

    Elmore, S. Apoptosis: a review of programmed cell death. Toxicol. Pathol. 35, 495–516 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Lubinska, L. Early course of Wallerian degeneration in myelinated fibres of the rat phrenic nerve. Brain Res. 130, 47–63 (1977).

    CAS  PubMed  Google Scholar 

  32. 32

    Wang, M., Wu, Y., Culver, D. G. & Glass, J. D. The gene for slow Wallerian degeneration (WldS) is also protective against vincristine neuropathy. Neurobiol. Dis. 8, 155–161 (2001).

    CAS  PubMed  Google Scholar 

  33. 33

    Samsam, M. et al. The WldS mutation delays robust loss of motor and sensory axons in a genetic model for myelin-related axonopathy. J. Neurosci. 23, 2833–2839 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Adalbert, R. et al. A rat model of slow Wallerian degeneration (WldS) with improved preservation of neuromuscular synapses. Eur. J. Neurosci. 21, 271–277 (2005).

    PubMed  Google Scholar 

  35. 35

    Martin, S. M., O'Brien, G. S., Portera-Cailliau, C. & Sagasti, A. Wallerian degeneration of zebrafish trigeminal axons in the skin is required for regeneration and developmental pruning. Development 137, 3985–3994 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Kitay, B. M., McCormack, R., Wang, Y., Tsoulfas, P. & Zhai, R. G. Mislocalization of neuronal mitochondria reveals regulation of Wallerian degeneration and NMNAT/WLDS mediated axon protection independent of axonal mitochondria. Hum. Mol. Genet. 22, 1601–1614 (2013). This study extends the evolutionary conservation of the WLDS-induced axon protection to human embryonic DRGs. It also reports that depriving axons of mitochondria slightly accelerates axon degeneration and is dispensable for the WLDS protective phenotype.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Wang, J. et al. A local mechanism mediates NAD-dependent protection of axon degeneration. J. Cell Biol. 170, 349–355 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Milde, S., Gilley, J. & Coleman, M. P. Subcellular localization determines the stability and axon protective capacity of axon survival factor Nmnat2. PLoS Biol. 11, e1001539 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Cohen, M. S., Ghosh, A. K., Kim, H. J., Jeon, N. L. & Jaffrey, S. R. Chemical genetic-mediated spatial regulation of protein expression in neurons reveals an axonal function for WldS. Chem. Biol. 19, 179–187 (2012). This study provides the most direct evidence supporting an axonal site of action for WLDS and NMNAT in delaying Wallerian degeneration. The stability of WLDS in axons isolated from their cell bodies by transection is shown to determine their survival time.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Fang, Y., Soares, L., Teng, X., Geary, M. & Bonini, N. M. A novel Drosophila model of nerve injury reveals an essential role of Nmnat in maintaining axonal integrity. Curr. Biol. 22, 590–595 (2012). This study shows that depletion of D. melanogaster dNmnat induces dying-back axon degeneration and that all three mammalian NMNAT isoforms as well as WLDS can rescue this phenotype when expressed ectopically. It also reports that depletion of mitochondria from axons abolishes these protective effects, consistent with but not proving a mitochondrial site of action.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Sasaki, Y. & Milbrandt, J. Axonal degeneration is blocked by nicotinamide mononucleotide adenylyltransferase (Nmnat) protein transduction into transected axons. J. Biol. Chem. 285, 41211–41215 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Vohra, B. P. S. et al. Amyloid precursor protein cleavage-dependent and -independent axonal degeneration programs share a common nicotinamide mononucleotide adenylyltransferase 1-sensitive pathway. J. Neurosci. 30, 13729–13738 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Nikolaev, A., McLaughlin, T., O'Leary, D. D. M. & Tessier-Lavigne, M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457, 981–989 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Simon, D. J. et al. A caspase cascade regulating developmental axon degeneration. J. Neurosci. 32, 17540–17553 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Schoenmann, Z. et al. Axonal degeneration is regulated by the apoptotic machinery or a NAD+-sensitive pathway in insects and mammals. J. Neurosci. 30, 6375–6386 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Araki, T., Sasaki, Y. & Milbrandt, J. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science 305, 1010–1013 (2004).

    CAS  PubMed  Google Scholar 

  47. 47

    Jia, H. et al. Identification of a critical site in Wlds: essential for Nmnat enzyme activity and axon-protective function. Neurosci. Lett. 413, 46–51 (2007).

    CAS  PubMed  Google Scholar 

  48. 48

    Avery, M. A., Sheehan, A. E., Kerr, K. S., Wang, J. & Freeman, M. R. WldS requires Nmnat1 enzymatic activity and N16–VCP interactions to suppress Wallerian degeneration. J. Cell Biol. 184, 501–513 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Conforti, L. et al. WldS protein requires Nmnat activity and a short N-terminal sequence to protect axons in mice. J. Cell Biol. 184, 491–500 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Sasaki, Y., Vohra, B. P. S., Lund, F. E. & Milbrandt, J. Nicotinamide mononucleotide adenylyl transferase-mediated axonal protection requires enzymatic activity but not increased levels of neuronal nicotinamide adenine dinucleotide. J. Neurosci. 29, 5525–5535 (2009). This report shows that although NMNAT activity is critical for delaying axon degeneration after injury, increasing neuronal NAD+ levels pharmacologically or genetically does not have the same effect. The authors propose that an unknown property of this enzyme activity other than NAD+ synthesis underlies the protective phenotype of NMNAT enzymes.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Yan, T. et al. Nmnat2 delays axon degeneration in superior cervical ganglia dependent on its NAD synthesis activity. Neurochem. Int. 56, 101–106 (2010).

    CAS  PubMed  Google Scholar 

  52. 52

    Sasaki, Y., Araki, T. & Milbrandt, J. Stimulation of nicotinamide adenine dinucleotide biosynthetic pathways delays axonal degeneration after axotomy. J. Neurosci. 26, 8484–8491 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Magnifico, S. et al. NAD+ acts on mitochondrial SirT3 to prevent axonal caspase activation and axonal degeneration. FASEB J. 27, 4712–4722 (2013).

    CAS  PubMed  Google Scholar 

  54. 54

    Conforti, L. et al. NAD+ and axon degeneration revisited: Nmnat1 cannot substitute for WldS to delay Wallerian degeneration. Cell Death Differ. 14, 116–127 (2007).

    CAS  PubMed  Google Scholar 

  55. 55

    Nikiforov, A., Dölle, C., Niere, M. & Ziegler, M. Pathways and subcellular compartmentation of NAD biosynthesis in human cells: from entry of extracellular precursors to mitochondrial NAD generation. J. Biol. Chem. 286, 21767–21778 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Shen, H., Hyrc, K. L. & Goldberg, M. P. Maintaining energy homeostasis is an essential component of WldS-mediated axon protection. Neurobiol. Dis. 59, 69–79 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Zhai, R. G. et al. Drosophila NMNAT maintains neural integrity independent of its NAD synthesis activity. PLoS Biol. 4, e416 (2006).

    PubMed  PubMed Central  Google Scholar 

  58. 58

    Zhai, R. G. et al. NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration. Nature 452, 887–891 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Ali, Y. O., Ruan, K. & Zhai, R. G. NMNAT suppresses tau-induced neurodegeneration by promoting clearance of hyperphosphorylated tau oligomers in a Drosophila model of tauopathy. Hum. Mol. Genet. 21, 237–250 (2012).

    CAS  PubMed  Google Scholar 

  60. 60

    Ali, Y. O., McCormack, R., Darr, A. & Zhai, R. G. Nicotinamide mononucleotide adenylyltransferase is a stress response protein regulated by the heat shock factor/hypoxia-inducible factor 1α pathway. J. Biol. Chem. 286, 19089–19099 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Ljungberg, M. C. et al. CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy. Hum. Mol. Genet. 21, 251–267 (2012).

    CAS  PubMed  Google Scholar 

  62. 62

    Rallis, A. et al. Molecular chaperones protect against JNK- and Nmnat-regulated axon degeneration in Drosophila. J. Cell Sci. 126, 838–849 (2012).

    PubMed  Google Scholar 

  63. 63

    Zang, S., Ali, Y. O., Ruan, K. & Zhai, R. G. Nicotinamide mononucleotide adenylyltransferase maintains active zone structure by stabilizing Bruchpilot. EMBO Rep. 14, 87–94 (2013).

    CAS  PubMed  Google Scholar 

  64. 64

    Gerdts, J., Summers, D. W., Sasaki, Y., DiAntonio, A. & Milbrandt, J. Sarm1-mediated axon degeneration requires both SAM and TIR interactions. J. Neurosci. 33, 13569–13580 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Yang, J. et al. Regulation of axon degeneration after injury and in development by the endogenous calpain inhibitor calpastatin. Neuron 80, 1175–1189 (2013).

    CAS  PubMed  Google Scholar 

  66. 66

    Kim, Y. et al. MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival. J. Exp. Med. 204, 2063–2074 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Lin, C.-W., Liu, H. Y., Chen, C.-Y. & Hsueh, Y.-P. Neuronally-expressed Sarm1 regulates expression of inflammatory and antiviral cytokines in brains. Innate Immun. 20, 161–172 (2014).

    PubMed  Google Scholar 

  68. 68

    Shin, J. E. et al. SCG10 is a JNK target in the axonal degeneration pathway. Proc. Natl Acad. Sci. USA 109, E3696–E3705 (2012).

    CAS  PubMed  Google Scholar 

  69. 69

    Miller, B. R. et al. A dual leucine kinase-dependent axon self-destruction program promotes Wallerian degeneration. Nature Neurosci. 12, 387–389 (2009).

    CAS  PubMed  Google Scholar 

  70. 70

    Di Paolo, G. et al. Differential distribution of stathmin and SCG10 in developing neurons in culture. J. Neurosci. Res. 50, 1000–1009 (1997).

    CAS  PubMed  Google Scholar 

  71. 71

    Lutjens, R. et al. Localization and targeting of SCG10 to the trans-Golgi apparatus and growth cone vesicles. Eur. J. Neurosci. 12, 2224–2234 (2000).

    CAS  PubMed  Google Scholar 

  72. 72

    Gerdts, J., Sasaki, Y., Vohra, B., Marasa, J. & Milbrandt, J. Image-based screening identifies novel roles for IKK and GSK3 in axonal degeneration. J. Biol. Chem. 286, 28011–28018 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Wakatsuki, S., Saitoh, F. & Araki, T. ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B-dependent CRMP2 phosphorylation. Nature Cell Biol. 13, 1415–1423 (2011).

    CAS  PubMed  Google Scholar 

  74. 74

    Ikegami, K., Kato, S. & Koike, T. N-α-p-tosyl-L-lysine chloromethyl ketone (TLCK) suppresses neuritic degeneration caused by different experimental paradigms including in vitro Wallerian degeneration. Brain Res. 1030, 81–93 (2004).

    CAS  PubMed  Google Scholar 

  75. 75

    George, E. B., Glass, J. D. & Griffin, J. W. Axotomy-induced axonal degeneration is mediated by calcium influx through ion-specific channels. J. Neurosci. 15, 6445–6452 (1995).

    CAS  PubMed  Google Scholar 

  76. 76

    Zhai, Q. et al. Involvement of the ubiquitin-proteasome system in the early stages of Wallerian degeneration. Neuron 39, 217–225 (2003).

    CAS  PubMed  Google Scholar 

  77. 77

    Adalbert, R. et al. Intra-axonal calcium changes after axotomy in wild-type and slow Wallerian degeneration axons. Neuroscience 225, 44–54 (2012).

    CAS  PubMed  Google Scholar 

  78. 78

    Ma, M. et al. Calpains mediate axonal cytoskeleton disintegration during Wallerian degeneration. Neurobiol. Dis. 56, 34–46 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Mishra, B., Carson, R., Hume, R. I. & Collins, C. A. Sodium and potassium currents influence wallerian degeneration of injured Drosophila axons. J. Neurosci. 33, 18728–18739 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Bhattacharya, M. R. C. et al. A model of toxic neuropathy in Drosophila reveals a role for MORN4 in promoting axonal degeneration. J. Neurosci. 32, 5054–5061 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Court, F. A. & Coleman, M. P. Mitochondria as a central sensor for axonal degenerative stimuli. Trends Neurosci. 35, 364–372 (2012).

    CAS  PubMed  Google Scholar 

  82. 82

    Sievers, C., Platt, N., Perry, V. H., Coleman, M. P. & Conforti, L. Neurites undergoing Wallerian degeneration show an apoptotic-like process with Annexin V positive staining and loss of mitochondrial membrane potential. Neurosci. Res. 46, 161–169 (2003).

    CAS  PubMed  Google Scholar 

  83. 83

    Beirowski, B. et al. Non-nuclear WldS determines its neuroprotective efficacy for axons and synapses in vivo. J. Neurosci. 29, 653–668 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Avery, M. A. et al. WldS prevents axon degeneration through increased mitochondrial flux and enhanced mitochondrial Ca2+ buffering. Curr. Biol. 22, 596–600 (2012). This study shows that mitochondria in WLDS flies are more motile and have a greater calcium buffering capability. It shows a partial reversal of the protective phenotype when Miro is used to reduce mitochondrial trafficking and proposes a protective mechanism involving these mitochondrial functions.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    O'Donnell, K. C., Vargas, M. E. & Sagasti, A. WldS and PGC-1 regulate mitochondrial transport and oxidation state after axonal injury. J. Neurosci. 33, 14778–14790 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Conforti, L. et al. Reducing expression of NAD+ synthesizing enzyme NMNAT1 does not affect the rate of Wallerian degeneration. FEBS J. 278, 2666–2679 (2011).

    CAS  PubMed  Google Scholar 

  87. 87

    Orsomando, G. et al. Simultaneous single-sample determination of NMNAT isozyme activities in mouse tissues. PLoS ONE 7, e53271 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Felici, R., Lapucci, A., Ramazzotti, M. & Chiarugi, A. Insight into molecular and functional properties of NMNAT3 reveals new hints of NAD homeostasis within human mitochondria. PLoS ONE 8, e76938 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Zala, D. et al. Vesicular glycolysis provides on-board energy for fast axonal transport. Cell 152, 479–491 (2013).

    CAS  PubMed  Google Scholar 

  90. 90

    Panneerselvam, P., Singh, L. P., Ho, B., Chen, J. & Ding, J. L. Targeting of pro-apoptotic TLR adaptor SARM to mitochondria: definition of the critical region and residues in the signal sequence. Biochem. J. 442, 263–271 (2012).

    CAS  PubMed  Google Scholar 

  91. 91

    Panneerselvam, P. et al. T-cell death following immune activation is mediated by mitochondria-localized SARM. Cell Death Differ. 20, 478–489 (2013).

    CAS  PubMed  Google Scholar 

  92. 92

    Mukherjee, P., Woods, T. A., Moore, R. A. & Peterson, K. E. Activation of the innate signaling molecule MAVS by Bunyavirus infection upregulates the adaptor protein SARM1, leading to neuronal death. Immunity 38, 705–716 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Barrientos, S. A. et al. Axonal degeneration is mediated by the mitochondrial permeability transition pore. J. Neurosci. 31, 966–978 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Nikic, I. et al. A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nature Med. 17, 495–499 (2011).

    CAS  PubMed  Google Scholar 

  95. 95

    Antenor-Dorsey, J. A. V. & O'Malley, K. L. WldS but not Nmnat1 protects dopaminergic neurites from MPP+ neurotoxicity. Mol. Neurodegener. 7, 5 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Press, C. & Milbrandt, J. Nmnat delays axonal degeneration caused by mitochondrial and oxidative stress. J. Neurosci. 28, 4861–4871 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Wagner, R., Heckman, H. M. & Myers, R. R. Wallerian degeneration and hyperalgesia after peripheral nerve injury are glutathione-dependent. Pain 77, 173–179 (1998).

    CAS  PubMed  Google Scholar 

  98. 98

    Calixto, A., Jara, J. S. & Court, F. A. Diapause formation and downregulation of insulin-like signaling via DAF-16/FOXO delays axonal degeneration and neuronal loss. PLoS Genet. 8, e1003141 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    López-Erauskin, J. et al. Antioxidants halt axonal degeneration in a mouse model of X-adrenoleukodystrophy. Ann. Neurol. 70, 84–92 (2011).

    PubMed  PubMed Central  Google Scholar 

  100. 100

    Finkel, T. & Holbrook, N. J. Oxidants, oxidative stress and the biology of ageing. Nature 408, 239–247 (2000).

    CAS  PubMed  Google Scholar 

  101. 101

    Horste, G. M. Z. et al. The Wlds transgene reduces axon loss in a Charcot-Marie-Tooth disease 1A rat model and nicotinamide delays post-traumatic axonal degeneration. Neurobiol. Dis. 42, 1–8 (2010).

    Google Scholar 

  102. 102

    Cheng, H.-C. & Burke, R. E. The WldS mutation delays anterograde, but not retrograde, axonal degeneration of the dopaminergic nigro-striatal pathway in vivo. J. Neurochem. 113, 683–691 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Zhu, Y., Zhang, L., Sasaki, Y., Milbrandt, J. & Gidday, J. M. Protection of mouse retinal ganglion cell axons and soma from glaucomatous and ischemic injury by cytoplasmic overexpression of nmnat1. Invest. Ophthalmol. Vis. Sci. 54, 25–36 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Bull, N. D., Chidlow, G., Wood, J. P. M., Martin, K. R. & Casson, R. J. The mechanism of axonal degeneration after perikaryal excitotoxic injury to the retina. Exp. Neurol. 236, 34–45 (2012).

    PubMed  Google Scholar 

  105. 105

    Stum, M. et al. An assessment of mechanisms underlying peripheral axonal degeneration caused by aminoacyl-tRNA synthetase mutations. Mol. Cell. Neurosci. 46, 432–443 (2011).

    CAS  PubMed  Google Scholar 

  106. 106

    Kariya, S., Mauricio, R., Dai, Y. & Monani, U. R. The neuroprotective factor Wlds fails to mitigate distal axonal and neuromuscular junction (NMJ) defects in mouse models of spinal muscular atrophy. Neurosci. Lett. 449, 246–251 (2009).

    CAS  PubMed  Google Scholar 

  107. 107

    Rose, F. F. et al. The Wallerian degeneration slow (Wlds) gene does not attenuate disease in a mouse model of spinal muscular atrophy. Biochem. Biophys. Res. Commun. 375, 119–123 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Zhu, X. et al. Mutations in a P-type ATPase gene cause axonal degeneration. PLoS Genet. 8, e1002853 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Zhu, S. S. et al. WldS protects against peripheral neuropathy and retinopathy in an experimental model of diabetes in mice. Diabetologia 54, 2440–2450 (2011).

    CAS  PubMed  Google Scholar 

  110. 110

    Wu, J. et al. WldS enhances insulin transcription and secretion via a SIRT1-dependent pathway and improves glucose homeostasis. Diabetes 60, 3197–3207 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Wang, C.-H. et al. Protective role of Wallerian degeneration slow (Wlds) gene against retinal ganglion cell body damage in a Wallerian degeneration model. Exp. Ther. Med. 5, 621–625 (2013).

    PubMed  Google Scholar 

  112. 112

    Verghese, P. B. et al. Nicotinamide mononucleotide adenylyl transferase 1 protects against acute neurodegeneration in developing CNS by inhibiting excitotoxic-necrotic cell death. Proc. Natl Acad. Sci. USA 108, 19054–19059 (2011).

    CAS  PubMed  Google Scholar 

  113. 113

    Gillingwater, T. H., Haley, J. E., Ribchester, R. R. & Horsburgh, K. Neuroprotection after transient global cerebral ischemia in Wlds mutant mice. J. Cereb. Blood Flow Metab. 24, 62–66 (2004).

    CAS  PubMed  Google Scholar 

  114. 114

    Tokunaga, S. & Araki, T. Wallerian degeneration slow mouse neurons are protected against cell death caused by mechanisms involving mitochondrial electron transport dysfunction. J. Neurosci. Res. 90, 664–671 (2012).

    CAS  PubMed  Google Scholar 

  115. 115

    Zhang, T. et al. Enzymes in the NAD+ salvage pathway regulate SIRT1 activity at target gene promoters. J. Biol. Chem. 284, 20408–20417 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Berger, F., Lau, C. & Ziegler, M. Regulation of poly(ADP-ribose) polymerase 1 activity by the phosphorylation state of the nuclear NAD biosynthetic enzyme NMN adenylyl transferase 1. Proc. Natl Acad. Sci. USA 104, 3765–3770 (2007).

    CAS  PubMed  Google Scholar 

  117. 117

    Fogh, I. et al. A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis. Hum. Mol. Genet. 23, 2220–2231 (2014).

    CAS  PubMed  Google Scholar 

  118. 118

    Parson, S. H. et al. Axotomy-dependent and -independent synapse elimination in organ cultures of Wlds mutant mouse skeletal muscle. J. Neurosci. Res. 76, 64–75 (2004).

    CAS  PubMed  Google Scholar 

  119. 119

    Bull, N. D., Guidi, A., Goedert, M., Martin, K. R. & Spillantini, M. G. Reduced axonal transport and increased excitotoxic retinal ganglion cell degeneration in mice transgenic for human mutant P301S tau. PLoS ONE 7, e34724 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Carty, M. et al. The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nature Immunol. 7, 1074–1081 (2006).

    CAS  Google Scholar 

  121. 121

    Zhou, X. et al. Molecular characterization of porcine SARM1 and its role in regulating TLRs signaling during highly pathogenic porcine reproductive and respiratory syndrome virus infection in vivo. Dev. Comp. Immunol. 39, 117–126 (2013).

    CAS  PubMed  Google Scholar 

  122. 122

    Szretter, K. J. et al. The immune adaptor molecule SARM modulates tumor necrosis factor α production and microglia activation in the brainstem and restricts West Nile Virus pathogenesis. J. Virol. 83, 9329–9338 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Lehmann, S. M. et al. An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nature Neurosci. 15, 827–835 (2012).

    CAS  PubMed  Google Scholar 

  124. 124

    Chen, C.-Y., Lin, C.-W., Chang, C.-Y., Jiang, S.-T. & Hsueh, Y.-P. Sarm1, a negative regulator of innate immunity, interacts with syndecan-2 and regulates neuronal morphology. J. Cell Biol. 193, 769–784 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    DiAntonio, A. et al. Ubiquitination-dependent mechanisms regulate synaptic growth and function. Nature 412, 449–452 (2001).

    CAS  PubMed  Google Scholar 

  126. 126

    Brown, M., Perry, V., Hunt, S. & Lapper, S. Further studies on motor and sensory nerve regeneration in mice with delayed Wallerian degeneration. Eur. J. Neurosci. 6, 420–428 (1994).

    CAS  PubMed  Google Scholar 

  127. 127

    Koyuncu, O. O., Perlman, D. H. & Enquist, L. W. Efficient retrograde transport of pseudorabies virus within neurons requires local protein synthesis in axons. Cell Host Microbe 13, 54–66 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Salegio, E. A. et al. Axonal transport of adeno-associated viral vectors is serotype-dependent. Gene Ther. 20, 348–352 (2013).

    CAS  PubMed  Google Scholar 

  129. 129

    Samuel, M. A., Wang, H., Siddharthan, V., Morrey, J. D. & Diamond, M. S. Axonal transport mediates West Nile virus entry into the central nervous system and induces acute flaccid paralysis. Proc. Natl Acad. Sci. USA 104, 17140–17145 (2007).

    CAS  PubMed  Google Scholar 

  130. 130

    Tsunoda, I. Axonal degeneration as a self-destructive defense mechanism against neurotropic virus infection. Future Virol. 3, 579–593 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Hoke, A. Animal models of peripheral neuropathies. Neurotherapeutics 9, 262–269 (2012).

    PubMed  PubMed Central  Google Scholar 

  132. 132

    Medana, I. M. & Esiri, M. M. Axonal damage: a key predictor of outcome in human CNS diseases. Brain 126, 515–530 (2003).

    CAS  PubMed  Google Scholar 

  133. 133

    Stys, P. K., Zamponi, G. W., van Minnen, J. & Geurts, J. J. G. Will the real multiple sclerosis please stand up? Nature Rev. Neurosci. 13, 507–514 (2012).

    CAS  Google Scholar 

  134. 134

    Nardo, G. et al. Transcriptomic indices of fast and slow disease progression in two mouse models of amyotrophic lateral sclerosis. Brain 136, 3305–3332 (2013).

    PubMed  Google Scholar 

  135. 135

    Groh, J. et al. Colony-stimulating factor-1 mediates macrophage-related neural damage in a model for Charcot-Marie-Tooth disease type 1X. Brain 135, 88–104 (2012).

    PubMed  Google Scholar 

  136. 136

    Koenekoop, R. K. et al. Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration. Nature Genet. 44, 1035–1039 (2012).

    CAS  PubMed  Google Scholar 

  137. 137

    Falk, M. J. et al. NMNAT1 mutations cause Leber congenital amaurosis. Nature Genet. 44, 1040–1045 (2012).

    CAS  PubMed  Google Scholar 

  138. 138

    Chiang, P.-W. et al. Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis. Nature Genet. 44, 972–974 (2012).

    CAS  PubMed  Google Scholar 

  139. 139

    Perrault, I. et al. Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy. Nature Genet. 44, 975–977 (2012).

    CAS  PubMed  Google Scholar 

  140. 140

    Magni, G. et al. Enzymology of NAD+ homeostasis in man. Cell. Mol. Life Sci. 61, 19–34 (2004).

    CAS  PubMed  Google Scholar 

  141. 141

    Di Stefano, M. & Conforti, L. Diversification of NAD biological role: the importance of location. FEBS J. 280, 4711–4728 (2013).

    CAS  PubMed  Google Scholar 

  142. 142

    Berger, F., Lau, C., Dahlmann, M. & Ziegler, M. Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms. J. Biol. Chem. 280, 36334–36341 (2005).

    CAS  PubMed  Google Scholar 

  143. 143

    Esposito, E. et al. The NAMPT inhibitor FK866 reverts the damage in spinal cord injury. J. Neuroinflammation 9, 66 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Meyer, H., Bug, M. & Bremer, S. Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nature Cell Biol. 14, 117–123 (2012).

    CAS  PubMed  Google Scholar 

  145. 145

    Lorber, B., Tassoni, A., Bull, N. D., Moschos, M. M. & Martin, K. R. Retinal ganglion cell survival and axon regeneration in WldS transgenic rats after optic nerve crush and lens injury. BMC Neurosci. 13, 56 (2012).

    PubMed  PubMed Central  Google Scholar 

  146. 146

    Carneiro, J. et al. The evolutionary portrait of metazoan NAD salvage. PLoS ONE 8, e64674 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Meyer zu Hörste, G. et al. The Wlds transgene reduces axon loss in a Charcot-Marie-Tooth disease 1A rat model and nicotinamide delays post-traumatic axonal degeneration. Neurobiol. Dis. 42, 1–8 (2011).

    PubMed  Google Scholar 

  148. 148

    Mi, W. et al. The slow Wallerian degeneration gene, WldS, inhibits axonal spheroid pathology in gracile axonal dystrophy mice. Brain 128, 405–416 (2005).

    PubMed  Google Scholar 

  149. 149

    Kaneko, S. et al. Protecting axonal degeneration by increasing nicotinamide adenine dinucleotide levels in experimental autoimmune encephalomyelitis models. J. Neurosci. 26, 9794–9804 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150

    Fischer, L. R. et al. The WldS gene modestly prolongs survival in the SOD1G93A fALS mouse. Neurobiol. Dis. 19, 293–300 (2005).

    CAS  PubMed  Google Scholar 

  151. 151

    Edgar, J. M. et al. Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia. J. Cell Biol. 166, 121–131 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Gültner, S., Laue, M., Riemer, C., Heise, I. & Baier, M. Prion disease development in slow Wallerian degeneration (WldS) mice. Neurosci. Lett. 456, 93–98 (2009).

    PubMed  Google Scholar 

  153. 153

    Edgar, J. M. et al. Early ultrastructural defects of axons and axon-glia junctions in mice lacking expression of Cnp1. Glia 57, 1815–1824 (2009).

    PubMed  Google Scholar 

Download references

Acknowledgements

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.).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Michael P. Coleman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

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.

Apoptosis

An active programme of cell death effected by caspases, a family of cysteine-dependent proteases, and regulated by BCL-2 family proteins.

MARCM

(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.

Palmitoylation

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.

FK866

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.

Chaperone

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.

Paranodes

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.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Further reading

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing