1932

Abstract

Significant advances have been made in recent years in identifying the genetic components of Wallerian degeneration, the process that brings the progressive destruction and removal of injured axons. It has now been accepted that Wallerian degeneration is an active and dynamic cellular process that is well regulated at molecular and cellular levels. In this review, we describe our current understanding of Wallerian degeneration, focusing on the molecular players and mechanisms that mediate the injury response, activate the degenerative program, transduce the death signal, execute the destruction order, and finally, clear away the debris. By highlighting the starring roles and sketching out the molecular script of Wallerian degeneration, we hope to provide a useful framework to understand Wallerian and Wallerian-like degeneration and to lay a foundation for developing new therapeutic strategies to treat axon degeneration in neural injury as well as in neurodegenerative disease.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-genet-071819-103917
2021-11-23
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/genet/55/1/annurev-genet-071819-103917.html?itemId=/content/journals/10.1146/annurev-genet-071819-103917&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Adalbert R, Morreale G, Paizs M, Conforti L, Walker SA et al. 2012. Intra-axonal calcium changes after axotomy in wild-type and slow Wallerian degeneration axons. Neuroscience 225:44–54
    [Google Scholar]
  2. 2. 
    Aldskogius H, Kozlova EN 1998. Central neuron–glial and glial–glial interactions following axon injury. Prog. Neurobiol. 55:1–26
    [Google Scholar]
  3. 3. 
    Anderson MA, Burda JE, Ren Y, Ao Y, O'Shea TM et al. 2016. Astrocyte scar formation aids central nervous system axon regeneration. Nature 532:195–200
    [Google Scholar]
  4. 4. 
    Avellino AM, Hart D, Dailey AT, Mackinnon M, Ellegala D, Kliot M. 1995. Differential macrophage responses in the peripheral and central nervous system during Wallerian degeneration of axons. Exp. Neurol. 136:183–98
    [Google Scholar]
  5. 5. 
    Avery MA, Rooney TM, Pandya JD, Wishart TM, Gillingwater TH et al. 2012. WldS prevents axon degeneration through increased mitochondrial flux and enhanced mitochondrial Ca2+ buffering. Curr. Biol. 22:596–600
    [Google Scholar]
  6. 6. 
    Avery MA, Sheehan AE, Kerr KS, Wang J, Freeman MR 2009. WldS requires Nmnat1 enzymatic activity and N16–VCP interactions to suppress Wallerian degeneration. J. Cell Biol. 184:501–13
    [Google Scholar]
  7. 7. 
    Babetto E, Beirowski B, Janeckova L, Brown R, Gilley J et al. 2010. Targeting NMNAT1 to axons and synapses transforms its neuroprotective potency in vivo. J. Neurosci. 30:13291–304
    [Google Scholar]
  8. 8. 
    Babetto E, Beirowski B, Russler EV, Milbrandt J, DiAntonio A. 2013. The Phr1 ubiquitin ligase promotes injury-induced axon self-destruction. Cell Rep 3:1422–29
    [Google Scholar]
  9. 9. 
    Babetto E, Wong KM, Beirowski B. 2020. A glycolytic shift in Schwann cells supports injured axons. Nat. Neurosci. 23:1215–28
    [Google Scholar]
  10. 10. 
    Barrientos SA, Martinez NW, Yoo S, Jara JS, Zamorano S et al. 2011. Axonal degeneration is mediated by the mitochondrial permeability transition pore. J. Neurosci. 31:966–78
    [Google Scholar]
  11. 11. 
    Bear MF, Connors BW, Paradiso MA. 2007. Neuroscience: Exploring the Brain. Philadelphia: Lippincott Williams and Wilkins. , 3rd ed..
  12. 12. 
    Bellver-Landete V, Bretheau F, Mailhot B, Vallières N, Lessard M et al. 2019. Microglia are an essential component of the neuroprotective scar that forms after spinal cord injury. Nat. Commun. 10:518
    [Google Scholar]
  13. 13. 
    Bendszus M, Stoll G. 2003. Caught in the act: in vivo mapping of macrophage infiltration in nerve injury by magnetic resonance imaging. J. Neurosci. 23:10892–96
    [Google Scholar]
  14. 14. 
    Berger F, Lau C, Dahlmann M, Ziegler M. 2005. Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms. J. Biol. Chem. 280:36334–41
    [Google Scholar]
  15. 15. 
    Blum ES, Abraham MC, Yoshimura S, Lu Y, Shaham S. 2012. Control of nonapoptotic developmental cell death in Caenorhabditis elegans by a polyglutamine-repeat protein. Science 335:970–73
    [Google Scholar]
  16. 16. 
    Bratkowski M, Xie T, Thayer DA, Lad S, Mathur P et al. 2020. Structural and mechanistic regulation of the pro-degenerative NAD hydrolase SARM1. Cell Rep. 32:107999
    [Google Scholar]
  17. 17. 
    Brosius Lutz A, Chung W-S, Sloan SA, Carson GA, Zhou L et al. 2017. Schwann cells use TAM receptor-mediated phagocytosis in addition to autophagy to clear myelin in a mouse model of nerve injury. PNAS 114:e8072–80
    [Google Scholar]
  18. 18. 
    Burke RE, O'Malley K. 2013. Axon degeneration in Parkinson's disease. Exp. Neurol. 246:72–83
    [Google Scholar]
  19. 19. 
    Buss A, Brook GA, Kakulas B, Martin D, Franzen R et al. 2004. Gradual loss of myelin and formation of an astrocytic scar during Wallerian degeneration in the human spinal cord. Brain 127:34–44
    [Google Scholar]
  20. 20. 
    Calixto A, Jara JS, Court FA. 2012. Diapause formation and downregulation of insulin-like signaling via DAF-16/FOXO delays axonal degeneration and neuronal loss. PLOS Genet 8:e1003141
    [Google Scholar]
  21. 21. 
    Cambronne XA, Kraus WL. 2020. Location, location, location: compartmentalization of NAD+ synthesis and functions in mammalian cells. Trends Biochem. Sci. 45:858–73
    [Google Scholar]
  22. 22. 
    Catenaccio A, Llavero Hurtado M, Diaz P, Lamont DJ, Wishart TM, Court FA 2017. Molecular analysis of axonal-intrinsic and glial-associated co-regulation of axon degeneration. Cell Death Dis 8:e3166
    [Google Scholar]
  23. 23. 
    Chen C-Y, Lin C-W, Chang C-Y, Jiang S-T, Hsueh Y-P. 2011. Sarm1, a negative regulator of innate immunity, interacts with syndecan-2 and regulates neuronal morphology. J. Cell Biol. 193:769–84
    [Google Scholar]
  24. 24. 
    Cheng H-C, Kim SR, Oo TF, Kareva T, Yarygina O et al. 2011. Akt suppresses retrograde degeneration of dopaminergic axons by inhibition of macroautophagy. J. Neurosci. 31:2125–35
    [Google Scholar]
  25. 25. 
    Chew DJ, Fawcett JW, Andrews MR. 2012. The challenges of long-distance axon regeneration in the injured CNS. Prog. Brain Res. 201:253–94
    [Google Scholar]
  26. 26. 
    Chiang P-W, Wang J, Chen Y, Fu Q, Zhong J et al. 2012. Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis. Nat. Genet. 44:972–74
    [Google Scholar]
  27. 27. 
    Coleman MP. 2005. Axon degeneration mechanisms: commonality amid diversity. Nat. Rev. Neurosci. 6:889–98
    [Google Scholar]
  28. 28. 
    Coleman MP, Freeman MR. 2010. Wallerian degeneration, WldS, and Nmnat. Annu. Rev. Neurosci. 33:245–67
    [Google Scholar]
  29. 29. 
    Coleman MP, Höke A. 2020. Programmed axon degeneration: from mouse to mechanism to medicine. Nat. Rev. Neurosci. 21:183–96
    [Google Scholar]
  30. 30. 
    Coleman MP, Ribchester RR. 2004. Programmed axon death, synaptic dysfunction and the ubiquitin proteasome system. Curr. Drug Targets CNS Neurol. Disord. 3:227–38
    [Google Scholar]
  31. 31. 
    Conforti L, Fang G, Beirowski B, Wang MS, Sorci L et al. 2007. NAD+ and axon degeneration revisited: Nmnat1 cannot substitute for WldS to delay Wallerian degeneration. Cell Death Differ 14:116–27
    [Google Scholar]
  32. 32. 
    Conforti L, Wilbrey A, Morreale G, Janeckova L, Beirowski B et al. 2009. WldS protein requires Nmnat activity and a short N-terminal sequence to protect axons in mice. J. Cell Biol. 184:491–500
    [Google Scholar]
  33. 33. 
    Couillault C, Pujol N, Reboul J, Sabatier L, Guichou JF et al. 2004. TLR-independent control of innate immunity in Caenorhabditis elegans by the TIR domain adaptor protein TIR-1, an ortholog of human SARM. Nat. Immunol. 5:488–94
    [Google Scholar]
  34. 34. 
    Davies AJ, Rinaldi S, Costigan M, Oh SB. 2020. Cytotoxic immunity in peripheral nerve injury and pain. Front. Neurosci. 14:142
    [Google Scholar]
  35. 35. 
    Deng Y, Huang H, Wang Y, Liu Z, Li N et al. 2015. A novel missense NMNAT1 mutation identified in a consanguineous family with Leber congenital amaurosis by targeted next generation sequencing. Gene 569:104–8
    [Google Scholar]
  36. 36. 
    Di Stefano M, Nascimento-Ferreira I, Orsomando G, Mori V, Gilley J et al. 2014. A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration. Cell Death Differ 22:731–42
    [Google Scholar]
  37. 37. 
    Ding C, Hammarlund M. 2019. Mechanisms of injury-induced axon degeneration. Curr. Opin. Neurobiol. 57:171–78
    [Google Scholar]
  38. 38. 
    Dixon JS. 1967.. “ Phagocytic” lysosomes in chromatolytic neurones. Nature 215:657–58
    [Google Scholar]
  39. 39. 
    Duncan GJ, Manesh SB, Hilton BJ, Assinck P, Plemel JR, Tetzlaff W. 2020. The fate and function of oligodendrocyte progenitor cells after traumatic spinal cord injury. Glia 68:227–45
    [Google Scholar]
  40. 40. 
    Elberg G, Liraz-Zaltsman S, Reichert F, Matozaki T, Tal M, Rotshenker S. 2019. Deletion of SIRPα (signal regulatory protein-α) promotes phagocytic clearance of myelin debris in Wallerian degeneration, axon regeneration, and recovery from nerve injury. J. Neuroinflammation 16:277
    [Google Scholar]
  41. 41. 
    Essuman K, Summers DW, Sasaki Y, Mao X, DiAntonio A, Milbrandt J. 2017. The SARM1 Toll/interleukin-1 receptor domain possesses intrinsic NAD+ cleavage activity that promotes pathological axonal degeneration. Neuron 93:1334–43.e5The first study to report that SARM1 has intrinsic NADase activity, which is required for triggering degeneration of injured axons.
    [Google Scholar]
  42. 42. 
    Essuman K, Summers DW, Sasaki Y, Mao X, Yim AKY et al. 2018. TIR domain proteins are an ancient family of NAD+-consuming enzymes. Curr. Biol. 28:421–30.e4
    [Google Scholar]
  43. 43. 
    Falk MJ, Zhang Q, Nakamaru-Ogiso E, Kannabiran C, Fonseca-Kelly Z et al. 2012. NMNAT1 mutations cause Leber congenital amaurosis. Nat. Genet. 44:1040–45
    [Google Scholar]
  44. 44. 
    Fang Y, Bonini NM. 2012. Axon degeneration and regeneration: insights from Drosophila models of nerve injury. Annu. Rev. Cell Dev. Biol. 28:575–97
    [Google Scholar]
  45. 45. 
    Fang Y, Soares L, Teng X, Geary M, Bonini NM. 2012. A novel Drosophila model of nerve injury reveals an essential role of Nmnat in maintaining axonal integrity. Curr. Biol. 22:590–95
    [Google Scholar]
  46. 46. 
    Farley JE, Burdett TC, Barria R, Neukomm LJ, Kenna KP et al. 2018. Transcription factor Pebbled/RREB1 regulates injury-induced axon degeneration. PNAS 115:1358–63
    [Google Scholar]
  47. 47. 
    Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV. 2004. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J. Neurosci. 24:2143–55
    [Google Scholar]
  48. 48. 
    Feng Y, Yan T, Zheng J, Ge X, Mu Y et al. 2010. Overexpression of WldS or Nmnat2 in Mauthner cells by single-cell electroporation delays axon degeneration in live zebrafish. J. Neurosci. Res. 88:3319–27
    [Google Scholar]
  49. 49. 
    Fiala JC, Harris KM 1999. Dendrite structure. Dendrites, Vol. 2 G Stuart, N Spruston, M Hausser 1–11 New York: Oxford Univ. Press
    [Google Scholar]
  50. 50. 
    Filous AR, Silver J. 2016. Targeting astrocytes in CNS injury and disease: a translational research approach. Prog. Neurobiol. 144:173–87
    [Google Scholar]
  51. 51. 
    Fitch MT, Silver J. 2008. CNS injury, glial scars, and inflammation: inhibitory extracellular matrices and regeneration failure. Exp. Neurol. 209:294–301
    [Google Scholar]
  52. 52. 
    Frati A, Cerretani D, Fiaschi AI, Frati P, Gatto V et al. 2017. Diffuse axonal injury and oxidative stress: a comprehensive review. Int. J. Mol. Sci. 18:2600
    [Google Scholar]
  53. 53. 
    George EB, Glass JD, Griffin JW. 1995. Axotomy-induced axonal degeneration is mediated by calcium influx through ion-specific channels. J. Neurosci. 15:6445–52
    [Google Scholar]
  54. 54. 
    George R, Griffin JW. 1994. Delayed macrophage responses and myelin clearance during Wallerian degeneration in the central nervous system: the dorsal radiculotomy model. Exp. Neurol. 129:225–36
    [Google Scholar]
  55. 55. 
    Gerdts J, Brace EJ, Sasaki Y, DiAntonio A, Milbrandt J. 2015. SARM1 activation triggers axon degeneration locally via NAD+ destruction. Science 348:453–57
    [Google Scholar]
  56. 56. 
    Gerdts J, Summers DW, Milbrandt J, DiAntonio A. 2016. Axon self-destruction: new links among SARM1, MAPKs, and NAD+ metabolism. Neuron 89:449–60
    [Google Scholar]
  57. 57. 
    Gerdts J, Summers DW, Sasaki Y, DiAntonio A, Milbrandt J 2013. Sarm1-mediated axon degeneration requires both SAM and TIR interactions. J. Neurosci. 33:13569–80This study demonstrates that SARM1 is pro-degenerative and that its SAM and TIR domains are required to promote WD.
    [Google Scholar]
  58. 58. 
    Gilley J, Coleman MP. 2010. Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons. PLOS Biol 8:e1000300
    [Google Scholar]
  59. 59. 
    Gilley J, Orsomando G, Nascimento-Ferreira I, Coleman MP. 2015. Absence of SARM1 rescues development and survival of NMNAT2-deficient axons. Cell Rep 10:1974–81
    [Google Scholar]
  60. 60. 
    Glass JD, Brushart TM, George EB, Griffin JW 1993. Prolonged survival of transected nerve fibres in C57BL/Ola mice is an intrinsic characteristic of the axon. J. Neurocytol. 22:311–21
    [Google Scholar]
  61. 61. 
    Gomez-Sanchez JA, Carty L, Iruarrizaga-Lejarreta M, Palomo-Irigoyen M, Varela-Rey M et al. 2015. Schwann cell autophagy, myelinophagy, initiates myelin clearance from injured nerves. J. Cell Biol. 210:153–68
    [Google Scholar]
  62. 62. 
    Gomez-Sanchez JA, Pilch KS, van der Lans M, Fazal SV, Benito C et al. 2017. After nerve injury, lineage tracing shows that myelin and Remak Schwann cells elongate extensively and branch to form repair Schwann cells, which shorten radically on remyelination. J. Neurosci. 37:9086–99
    [Google Scholar]
  63. 63. 
    Greenhalgh AD, David S. 2014. Differences in the phagocytic response of microglia and peripheral macrophages after spinal cord injury and its effects on cell death. J. Neurosci. 34:6316–22
    [Google Scholar]
  64. 64. 
    Grossman SD, Rosenberg LJ, Wrathall JR. 2001. Temporal-spatial pattern of acute neuronal and glial loss after spinal cord contusion. Exp. Neurol. 168:273–82
    [Google Scholar]
  65. 65. 
    Hill CS, Coleman MP, Menon DK. 2016. Traumatic axonal injury: mechanisms and translational opportunities. Trends Neurosci 39:311–24
    [Google Scholar]
  66. 66. 
    Horsefield S, Burdett H, Zhang X, Manik MK, Shi Y et al. 2019. NAD+ cleavage activity by animal and plant TIR domains in cell death pathways. Science 365:793–99
    [Google Scholar]
  67. 67. 
    Jang SY, Shin YK, Park SY, Park JY, Lee HJ et al. 2016. Autophagic myelin destruction by Schwann cells during Wallerian degeneration and segmental demyelination. Glia 64:730–42
    [Google Scholar]
  68. 68. 
    Jiang Y, Liu T, Lee CH, Chang Q, Yang J, Zhang Z 2020. The NAD+-mediated self-inhibition mechanism of pro-neurodegenerative SARM1. Nature 588:658–63
    [Google Scholar]
  69. 69. 
    Johnson VE, Stewart W, Smith DH. 2013. Axonal pathology in traumatic brain injury. Exp. Neurol. 246:35–43
    [Google Scholar]
  70. 70. 
    Jones LL, Margolis RU, Tuszynski MH 2003. The chondroitin sulfate proteoglycans neurocan, brevican, phosphacan, and versican are differentially regulated following spinal cord injury. Exp. Neurol. 182:399–411
    [Google Scholar]
  71. 71. 
    Kim KH, Lee M-S. 2014. Autophagy—a key player in cellular and body metabolism. Nat. Rev. Endocrinol. 10:322–37
    [Google Scholar]
  72. 72. 
    Kim Y, Zhou P, Qian L, Chuang JZ, Lee J et al. 2007. MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival. J. Exp. Med. 204:2063–74
    [Google Scholar]
  73. 73. 
    Kinoshita Y, Kondo S, Takahashi K, Nagai J, Wakatsuki S et al. 2019. Genetic inhibition of CRMP2 phosphorylation delays Wallerian degeneration after optic nerve injury. Biochem. Biophys. Res. Commun. 514:1037–39
    [Google Scholar]
  74. 74. 
    Kiryu-Seo S, Kiyama H. 2019. Mitochondrial behavior during axon regeneration/degeneration in vivo. Neurosci. Res. 139:42–47
    [Google Scholar]
  75. 75. 
    Knoferle J, Koch JC, Ostendorf T, Michel U, Planchamp V et al. 2010. Mechanisms of acute axonal degeneration in the optic nerve in vivo. PNAS 107:6064–69
    [Google Scholar]
  76. 76. 
    Koenekoop RK, Wang H, Majewski J, Wang X, Lopez I et al. 2012. Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration. Nat. Genet. 44:1035–39
    [Google Scholar]
  77. 77. 
    Krauss R, Bosanac T, Devraj R, Engber T, Hughes RO. 2020. Axons matter: the promise of treating neurodegenerative disorders by targeting SARM1-mediated axonal degeneration. Trends Pharmacol. Sci. 41:281–93
    [Google Scholar]
  78. 78. 
    Kurek JB, Austin L, Cheema SS, Bartlett PF, Murphy M. 1996. Up-regulation of leukaemia inhibitory factor and interleukin-6 in transected sciatic nerve and muscle following denervation. Neuromuscul. Disord. 6:105–14
    [Google Scholar]
  79. 79. 
    Kurz CL, Shapira M, Chen K, Baillie DL, Tan MW. 2007. Caenorhabditis elegans pgp-5 is involved in resistance to bacterial infection and heavy metal and its regulation requires TIR-1 and a p38 map kinase cascade. Biochem. Biophys. Res. Commun. 363:438–43
    [Google Scholar]
  80. 80. 
    Lautrup S, Sinclair DA, Mattson MP, Fang EF. 2019. NAD+ in brain aging and neurodegenerative disorders. Cell Metab 30:630–55
    [Google Scholar]
  81. 81. 
    Liu HW, Smith CB, Schmidt MS, Cambronne XA, Cohen MS et al. 2018. Pharmacological bypass of NAD+ salvage pathway protects neurons from chemotherapy-induced degeneration. PNAS 115:10654–59
    [Google Scholar]
  82. 82. 
    Loreto A, Di Stefano M, Gering M, Conforti L. 2015. Wallerian degeneration is executed by an NMN-SARM1-dependent late Ca2+ influx but only modestly influenced by mitochondria. Cell Rep 13:2539–52
    [Google Scholar]
  83. 83. 
    Lunn ER, Perry VH, Brown MC, Gordon S 1989. Absence of Wallerian degeneration does not hinder regeneration in peripheral nerve. Eur. J. Neurosci. 1:27–33The first study to describe the WLDS mice, in which degeneration of injured axons is substantially delayed.
    [Google Scholar]
  84. 84. 
    Ma M. 2013. Role of calpains in the injury-induced dysfunction and degeneration of the mammalian axon. Neurobiol. Dis. 60:61–79
    [Google Scholar]
  85. 85. 
    Ma M, Ferguson TA, Schoch KM, Li J, Qian Y et al. 2013. Calpains mediate axonal cytoskeleton disintegration during Wallerian degeneration. Neurobiol. Dis. 56:34–46
    [Google Scholar]
  86. 86. 
    Ma X, Zhu Y, Lu J, Xie J, Li C et al. 2020. Nicotinamide mononucleotide adenylyltransferase uses its NAD+ substrate-binding site to chaperone phosphorylated Tau. eLife 9:e51859
    [Google Scholar]
  87. 87. 
    Mack TG, Reiner M, Beirowski B, Mi W, Emanuelli M et al. 2001. Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene. Nat. Neurosci. 4:1199–206This study identifies the UBE4B-NMNAT1 fusion encoded by the WLDS mutant allele counts for the axoprotection in WLDS mice.
    [Google Scholar]
  88. 88. 
    Martin SM, O'Brien GS, Portera-Cailliau C, Sagasti A. 2010. Wallerian degeneration of zebrafish trigeminal axons in the skin is required for regeneration and developmental pruning. Development 137:3985–94
    [Google Scholar]
  89. 89. 
    Matthews MR, Raisman G. 1972. A light and electron microscopic study of the cellular response to axonal injury in the superior cervical ganglion of the rat. Proc. R. Soc. B 181:43–79
    [Google Scholar]
  90. 90. 
    McKeon RJ, Jurynec MJ, Buck CR. 1999. The chondroitin sulfate proteoglycans neurocan and phosphacan are expressed by reactive astrocytes in the chronic CNS glial scar. J. Neurosci. 19:10778–88
    [Google Scholar]
  91. 91. 
    Menzies FM, Fleming A, Rubinsztein DC. 2015. Compromised autophagy and neurodegenerative diseases. Nat. Rev. Neurosci. 16:345–57
    [Google Scholar]
  92. 92. 
    Miller BR, Press C, Daniels RW, Sasaki Y, Milbrandt J, DiAntonio A. 2009. A dual leucine kinase-dependent axon self-destruction program promotes Wallerian degeneration. Nat. Neurosci. 12:387–89
    [Google Scholar]
  93. 93. 
    Mishra B, Carson R, Hume RI, Collins CA. 2013. Sodium and potassium currents influence Wallerian degeneration of injured Drosophila axons. J. Neurosci. 33:18728–39
    [Google Scholar]
  94. 94. 
    Mizushima N, Komatsu M. 2011. Autophagy: renovation of cells and tissues. Cell 147:728–41
    [Google Scholar]
  95. 95. 
    Mizushima N, Levine B, Cuervo AM, Klionsky DJ. 2008. Autophagy fights disease through cellular self-digestion. Nature 451:1069–75
    [Google Scholar]
  96. 96. 
    Moldovan M, Alvarez S, Krarup C 2009. Motor axon excitability during Wallerian degeneration. Brain 132:511–23
    [Google Scholar]
  97. 97. 
    Mukherjee P, Woods TA, Moore RA, Peterson KE. 2013. Activation of the innate signaling molecule MAVS by Bunyavirus infection upregulates the adaptor protein SARM1, leading to neuronal death. Immunity 38:705–16
    [Google Scholar]
  98. 98. 
    Murata H, Khine CC, Nishikawa A, Yamamoto KI, Kinoshita R, Sakaguchi M. 2018. c-Jun N-terminal kinase (JNK)-mediated phosphorylation of SARM1 regulates NAD+ cleavage activity to inhibit mitochondrial respiration. J. Biol. Chem. 293:18933–43
    [Google Scholar]
  99. 99. 
    Murinson BB, Archer DR, Li Y, Griffin JW. 2005. Degeneration of myelinated efferent fibers prompts mitosis in Remak Schwann cells of uninjured C-fiber afferents. J. Neurosci. 25:1179–87
    [Google Scholar]
  100. 100. 
    Namikawa K, Fukushima M, Murakami K, Suzuki A, Takasawa S et al. 2005. Expression of Reg/PAP family members during motor nerve regeneration in rat. Biochem. Biophys. Res. Commun. 332:126–34
    [Google Scholar]
  101. 101. 
    Namikawa K, Okamoto T, Suzuki A, Konishi H, Kiyama H. 2006. Pancreatitis-associated protein-III is a novel macrophage chemoattractant implicated in nerve regeneration. J. Neurosci. 26:7460–67
    [Google Scholar]
  102. 102. 
    Napoli I, Noon LA, Ribeiro S, Kerai AP, Parrinello S et al. 2012. A central role for the ERK-signaling pathway in controlling Schwann cell plasticity and peripheral nerve regeneration in vivo. Neuron 73:729–42
    [Google Scholar]
  103. 103. 
    Neukomm LJ, Burdett TC, Seeds AM, Hampel S, Coutinho-Budd JC et al. 2017. Axon death pathways converge on Axundead to promote functional and structural axon disassembly. Neuron 95:78–91.e5
    [Google Scholar]
  104. 104. 
    Nichols ALA, Meelkop E, Linton C, Giordano-Santini R, Sullivan RK et al. 2016. The apoptotic engulfment machinery regulates axonal degeneration in C. elegans neurons. Cell Rep 14:1673–83
    [Google Scholar]
  105. 105. 
    Norrmén C, Figlia G, Pfistner P, Pereira JA, Bachofner S, Suter U. 2018. mTORC1 is transiently reactivated in injured nerves to promote c-Jun elevation and Schwann cell dedifferentiation. J. Neurosci. 38:4811–28
    [Google Scholar]
  106. 106. 
    O'Donnell KC, Vargas ME, Sagasti A. 2013. WldS and PGC-1α regulate mitochondrial transport and oxidation state after axonal injury. J. Neurosci. 33:14778–90
    [Google Scholar]
  107. 107. 
    Osterloh JM, Yang J, Rooney TM, Fox AN, Adalbert R et al. 2012. dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science 337:481–84This study reveals that the LOF of SARM1 provides axonal protection in nerve injury.
    [Google Scholar]
  108. 108. 
    Panneerselvam P, Singh LP, Selvarajan V, Chng WJ, Ng SB et al. 2013. T-cell death following immune activation is mediated by mitochondria-localized SARM. Cell Death Differ 20:478–89
    [Google Scholar]
  109. 109. 
    Park JY, Jang SY, Shin YK, Koh H, Suh DJ et al. 2013. Mitochondrial swelling and microtubule depolymerization are associated with energy depletion in axon degeneration. Neuroscience 238:258–69
    [Google Scholar]
  110. 110. 
    Penas C, Font-Nieves M, Forés J, Petegnief V, Planas A et al. 2011. Autophagy, and BiP level decrease are early key events in retrograde degeneration of motoneurons. Cell Death Differ 18:1617–27
    [Google Scholar]
  111. 111. 
    Perry VH, Brown MC, Gordon S 1987. The macrophage response to central and peripheral nerve injury. A possible role for macrophages in regeneration. J. Exp. Med. 165:1218–23
    [Google Scholar]
  112. 112. 
    Press C, Milbrandt J. 2008. Nmnat delays axonal degeneration caused by mitochondrial and oxidative stress. J. Neurosci. 28:4861–71
    [Google Scholar]
  113. 113. 
    Purice MD, Speese SD, Logan MA. 2016. Delayed glial clearance of degenerating axons in aged Drosophila is due to reduced PI3K/Draper activity. Nat. Commun. 7:12871
    [Google Scholar]
  114. 114. 
    Rabchevsky AG, Sullivan PG, Scheff SW. 2007. Temporal-spatial dynamics in oligodendrocyte and glial progenitor cell numbers throughout ventrolateral white matter following contusion spinal cord injury. Glia 55:831–43
    [Google Scholar]
  115. 115. 
    Ribas VT, Schnepf B, Challagundla M, Koch JC, Bähr M, Lingor P. 2015. Early and sustained activation of autophagy in degenerating axons after spinal cord injury. Brain Pathol 25:157–70
    [Google Scholar]
  116. 116. 
    Rogov V, Dotsch V, Johansen T, Kirkin V. 2014. Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. Mol. Cell 53:167–78
    [Google Scholar]
  117. 117. 
    Rolls MM, Thyagarajan P, Feng C. 2020. Microtubule dynamics in healthy and injured neurons. Dev. Neurobiol. 81:321–32
    [Google Scholar]
  118. 118. 
    Rosenberg AF, Wolman MA, Franzini-Armstrong C, Granato M. 2012. In vivo nerve–macrophage interactions following peripheral nerve injury. J. Neurosci. 32:3898–909
    [Google Scholar]
  119. 119. 
    Rotshenker S. 2011. Wallerian degeneration: the innate-immune response to traumatic nerve injury. J. Neuroinflamm. 8:109
    [Google Scholar]
  120. 120. 
    Sasaki Y, Engber TM, Hughes RO, Figley MD, Wu T et al. 2020. cADPR is a gene dosage-sensitive biomarker of SARM1 activity in healthy, compromised, and degenerating axons. Exp. Neurol. 329:113252
    [Google Scholar]
  121. 121. 
    Sasaki Y, Milbrandt J. 2010. Axonal degeneration is blocked by nicotinamide mononucleotide adenylyltransferase (Nmnat) protein transduction into transected axons. J. Biol. Chem. 285:41211–15
    [Google Scholar]
  122. 122. 
    Sasaki Y, Nakagawa T, Mao X, DiAntonio A, Milbrandt J 2016. NMNAT1 inhibits axon degeneration via blockade of SARM1-mediated NAD+ depletion. eLife 5:e19749
    [Google Scholar]
  123. 123. 
    Sasaki Y, Vohra BP, Baloh RH, Milbrandt J. 2009. Transgenic mice expressing the Nmnat1 protein manifest robust delay in axonal degeneration in vivo. J. Neurosci. 29:6526–34
    [Google Scholar]
  124. 124. 
    Sasaki Y, Vohra BP, Lund FE, Milbrandt J. 2009. Nicotinamide mononucleotide adenylyl transferase-mediated axonal protection requires enzymatic activity but not increased levels of neuronal nicotinamide adenine dinucleotide. J. Neurosci. 29:5525–35
    [Google Scholar]
  125. 125. 
    Schlaepfer WW, Zimmerman U-JP. 1985. Mechanisms underlying the neuronal response to ischemic injury. Calcium-activated proteolysis of neurofilaments. Prog. Brain Res. 63:185–96
    [Google Scholar]
  126. 126. 
    Shen C, Vohra M, Zhang P, Mao X, Figley MD et al. 2021. Multiple domain interfaces mediate SARM1 autoinhibition. PNAS 118:e2023151118
    [Google Scholar]
  127. 127. 
    Sheng Z-H. 2017. The interplay of axonal energy homeostasis and mitochondrial trafficking and anchoring. Trends Cell Biol 27:403–16
    [Google Scholar]
  128. 128. 
    Shin JE, Miller BR, Babetto E, Cho Y, Sasaki Y et al. 2012. SCG10 is a JNK target in the axonal degeneration pathway. PNAS 109:e3696–3705
    [Google Scholar]
  129. 129. 
    Sievers C, Platt N, Perry VH, Coleman MP, Conforti L. 2003. Neurites undergoing Wallerian degeneration show an apoptotic-like process with annexin V positive staining and loss of mitochondrial membrane potential. Neurosci. Res. 46:161–69
    [Google Scholar]
  130. 130. 
    Smith RS, Bisby MA. 1993. Persistence of axonal transport in isolated axons of the mouse. Eur. J. Neurosci. 5:1127–35
    [Google Scholar]
  131. 131. 
    Sporny M, Guez-Haddad J, Khazma T, Yaron A, Dessau M et al. 2020. The structural basis for SARM1 inhibition and activation under energetic stress. eLife 9:e62021
    [Google Scholar]
  132. 132. 
    Sporny M, Guez-Haddad J, Lebendiker M, Ulisse V, Volf A et al. 2019. Structural evidence for an octameric ring arrangement of SARM1. J. Mol. Biol. 431:3591–605
    [Google Scholar]
  133. 133. 
    Summers DW, Milbrandt J, DiAntonio A 2018. Palmitoylation enables MAPK-dependent proteostasis of axon survival factors. PNAS 115:e8746–54
    [Google Scholar]
  134. 134. 
    Takaso Y, Noda M, Hattori T, Roboon J, Hatano M et al. 2020. Deletion of CD38 and supplementation of NAD+ attenuate axon degeneration in a mouse facial nerve axotomy model. Sci. Rep. 10:17795
    [Google Scholar]
  135. 135. 
    Tian W, Czopka T, López-Schier H. 2020. Systemic loss of Sarm1 protects Schwann cells from chemotoxicity by delaying axon degeneration. Commun. Biol. 3:49
    [Google Scholar]
  136. 136. 
    Tofaris GK, Patterson PH, Jessen KR, Mirsky R. 2002. Denervated Schwann cells attract macrophages by secretion of leukemia inhibitory factor (LIF) and monocyte chemoattractant protein-1 in a process regulated by interleukin-6 and LIF. J. Neurosci. 22:6696–703
    [Google Scholar]
  137. 137. 
    Tooze SA, Schiavo G. 2008. Liaisons dangereuses: autophagy, neuronal survival and neurodegeneration. Curr. Opin. Neurobiol. 18:504–15
    [Google Scholar]
  138. 138. 
    Toy D, Namgung U. 2013. Role of glial cells in axonal regeneration. Exp. Neurobiol. 22:68–76
    [Google Scholar]
  139. 139. 
    Tripathi R, McTigue DM. 2007. Prominent oligodendrocyte genesis along the border of spinal contusion lesions. Glia 55:698–711
    [Google Scholar]
  140. 140. 
    Tsutsui S, Stys PK. 2013. Metabolic injury to axons and myelin. Exp. Neurol. 246:26–34
    [Google Scholar]
  141. 141. 
    Vahsen BF, Ribas VT, Sundermeyer J, Boecker A, Dambeck V et al. 2020. Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing. Cell Death Differ 27:2810–27
    [Google Scholar]
  142. 142. 
    Vargas ME, Barres BA. 2007. Why is Wallerian degeneration in the CNS so slow?. Annu. Rev. Neurosci. 30:153–79
    [Google Scholar]
  143. 143. 
    Vargas ME, Yamagishi Y, Tessier-Lavigne M, Sagasti A. 2015. Live imaging of calcium dynamics during axon degeneration reveals two functionally distinct phases of calcium influx. J. Neurosci. 35:15026–38
    [Google Scholar]
  144. 144. 
    Verdin E. 2015. NAD+ in aging, metabolism, and neurodegeneration. Science 350:1208–13
    [Google Scholar]
  145. 145. 
    Vial JD. 1958. The early changes in the axoplasm during Wallerian degeneration. J. Biophys. Biochem. Cytol. 4:551–55
    [Google Scholar]
  146. 146. 
    Villegas R, Martinez NW, Lillo J, Pihan P, Hernandez D et al. 2014. Calcium release from intra-axonal endoplasmic reticulum leads to axon degeneration through mitochondrial dysfunction. J. Neurosci. 34:7179–89
    [Google Scholar]
  147. 147. 
    Wakatsuki S, Saitoh F, Araki T. 2011. ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B-dependent CRMP2 phosphorylation. Nat. Cell. Biol. 13:1415–23
    [Google Scholar]
  148. 148. 
    Wakatsuki S, Tokunaga S, Shibata M, Araki T. 2017. GSK3B-mediated phosphorylation of MCL1 regulates axonal autophagy to promote Wallerian degeneration. J. Cell Biol. 216:477–93
    [Google Scholar]
  149. 149. 
    Walker LJ, Summers DW, Sasaki Y, Brace EJ, Milbrandt J, DiAntonio A 2017. MAPK signaling promotes axonal degeneration by speeding the turnover of the axonal maintenance factor NMNAT2. eLife 6:e22540
    [Google Scholar]
  150. 150. 
    Waller A. 1850. 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. Philos. Trans. R. Soc. 140:423–29
    [Google Scholar]
  151. 151. 
    Wan L, Essuman K, Anderson RG, Sasaki Y, Monteiro F et al. 2019. TIR domains of plant immune receptors are NAD+-cleaving enzymes that promote cell death. Science 365:799–803
    [Google Scholar]
  152. 152. 
    Wang H, Wang X, Zhang K, Wang Q, Cao X et al. 2019. Rapid depletion of ESCRT protein Vps4 underlies injury-induced autophagic impediment and Wallerian degeneration. Sci. Adv. 5:eaav4971This study demonstrates that promoting autophagic flux by overexpression of Vps4, an NAD+-independent mechanism, can attenuate injury-induced axon degeneration.
    [Google Scholar]
  153. 153. 
    Wang J, Zhai Q, Chen Y, Lin E, Gu W et al. 2005. A local mechanism mediates NAD-dependent protection of axon degeneration. J. Cell Biol. 170:349–55
    [Google Scholar]
  154. 154. 
    Wang QJ, Ding Y, Kohtz S, Mizushima N, Cristea IM et al. 2006. Induction of autophagy in axonal dystrophy and degeneration. J. Neurosci. 26:8057–68
    [Google Scholar]
  155. 155. 
    Wen Y, Parrish JZ, He R, Zhai RG, Kim MD. 2011. Nmnat exerts neuroprotective effects in dendrites and axons. Mol. Cell. Neurosci. 48:1–8
    [Google Scholar]
  156. 156. 
    Xiong X, Hao Y, Sun K, Li J, Li X et al. 2012. The Highwire ubiquitin ligase promotes axonal degeneration by tuning levels of Nmnat protein. PLOS Biol 10:e1001440
    [Google Scholar]
  157. 157. 
    Xiong X, Wang X, Ewanek R, Bhat P, DiAntonio A, Collins CA. 2010. Protein turnover of the Wallenda/DLK kinase regulates a retrograde response to axonal injury. J. Cell Biol. 191:211–23
    [Google Scholar]
  158. 158. 
    Yahata N, Yuasa S, Araki T. 2009. Nicotinamide mononucleotide adenylyltransferase expression in mitochondrial matrix delays Wallerian degeneration. J. Neurosci. 29:6276–84
    [Google Scholar]
  159. 159. 
    Yamagishi Y, Tessier-Lavigne M. 2016. An atypical SCF-like ubiquitin ligase complex promotes Wallerian degeneration through regulation of axonal Nmnat2. Cell Rep 17:774–82
    [Google Scholar]
  160. 160. 
    Yan D, Wu Z, Chisholm AD, Jin Y 2009. The DLK-1 kinase promotes mRNA stability and local translation in C. elegans synapses and axon regeneration. Cell 138:1005–18
    [Google Scholar]
  161. 161. 
    Yang J, Weimer RM, Kallop D, Olsen O, Wu Z et al. 2013. Regulation of axon degeneration after injury and in development by the endogenous calpain inhibitor calpastatin. Neuron 80:1175–89
    [Google Scholar]
  162. 162. 
    Yang J, Wu Z, Renier N, Simon DJ, Uryu K et al. 2015. Pathological axonal death through a MAPK cascade that triggers a local energy deficit. Cell 160:161–76This work systematically examines the function of the MAPK signaling pathway in WD.
    [Google Scholar]
  163. 163. 
    Yang Y, Coleman M, Zhang L, Zheng X, Yue Z. 2013. Autophagy in axonal and dendritic degeneration. Trends Neurosci 36:418–28
    [Google Scholar]
  164. 164. 
    Yang Y, Fukui K, Koike T, Zheng X. 2007. Induction of autophagy in neurite degeneration of mouse superior cervical ganglion neurons. Eur. J. Neurosci. 26:2979–88
    [Google Scholar]
  165. 165. 
    Zhai RG, Zhang F, Hiesinger PR, Cao Y, Haueter CM, Bellen HJ. 2008. NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration. Nature 452:887–91
    [Google Scholar]
  166. 166. 
    Zhang XQ, Lu JT, Jiang WX, Lu YB, Wu M et al. 2015. NAMPT inhibitor and metabolite protect mouse brain from cryoinjury through distinct mechanisms. Neuroscience 291:230–40
    [Google Scholar]
  167. 167. 
    Zhao ZY, Xie XJ, Li WH, Liu J, Chen Z et al. 2019. A cell-permeant mimetic of NMN activates SARM1 to produce cyclic ADP-ribose and induce non-apoptotic cell death. iScience 15:452–66
    [Google Scholar]
/content/journals/10.1146/annurev-genet-071819-103917
Loading
/content/journals/10.1146/annurev-genet-071819-103917
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error