Abstract
The action potential conduction along the axon is highly dependent on the healthy interactions between the axon and myelin-producing glial cells. Myelin, which facilitates action potential, is the protective insulation around the axon formed by Schwann cells and oligodendrocytes in the peripheral (PNS) and central nervous system (CNS), respectively. Myelin is a continuous structure with intermittent gaps called nodes of Ranvier, which are the sites enriched with ion channels, transmembrane, scaffolding, and cytoskeletal proteins. Decades-long extensive research has identified a comprehensive proteome with strictly regularized localization at the node of Ranvier. Concurrently, axon-glia interactions at the node of Ranvier have gathered significant attention as the pathophysiological targets for various neurodegenerative disorders. Numerous studies have shown the alterations in the axon-glia interactions culminating in neurological diseases. In this review, we have provided an update on the molecular composition of the node of Ranvier. Further, we have discussed in detail the consequences of disruption of axon-glia interactions during the pathogenesis of various CNS and PNS disorders.
Graphical Abstract
Similar content being viewed by others
References
Amor V, Zhang C, Vainshtein A, Zhang A, Zollinger DR, Eshed-Eisenbach Y, Brophy PJ, Rasband MN, Peles E (2017) The paranodal cytoskeleton clusters Na+ channels at nodes of Ranvier. Elife 6:e21392
Azevedo CJ, Cen SY, Khadka S, Liu S, Kornak J, Shi Y, Zheng L, Hauser SL, Pelletier D (2018) Thalamic atrophy in multiple sclerosis: a magnetic resonance imaging marker of neurodegeneration throughout disease. Ann Neurol 83:223–234
Bakkaloglu B, O’Roak BJ, Louvi A, Gupta AR, Abelson JF, Morgan TM, Chawarska K, Klin A, Ercan-Sencicek AG, Stillman AA (2008) Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am J Hum Genet 82:165–173
Bartzokis G (2011) Alzheimer’s disease as homeostatic responses to age-related myelin breakdown. Neurobiol Aging 32:1341–1371
Baruch K, Silberberg G, Aviv A, Shamir E, Bening-Abu-Shach U, Baruch Y, Darvasi A, Navon R (2009) Association between golli-MBP and schizophrenia in the Jewish Ashkenazi population: are regulatory regions involved? Int J Neuropsychopharmacol 12:885–894
Bekku Y, Rauch U, Ninomiya Y, Oohashi T (2009) Brevican distinctively assembles extracellular components at the large diameter nodes of Ranvier in the CNS. J Neurochem 108:1266–1276
Ben-Shalom R, Keeshen CM, Berrios KN, An JY, Sanders SJ, Bender KJ (2017) Opposing effects on NaV1. 2 function underlie differences between SCN2A variants observed in individuals with autism spectrum disorder or infantile seizures. Biol Psychiat 82:224–232
Bhat MA, Rios JC, Lu Y, Garcia-Fresco GP, Ching W, Martin MS, Li J, Einheber S, Chesler M, Rosenbluth J (2001) Axon-glia interactions and the domain organization of myelinated axons requires neurexin IV/Caspr/Paranodin. Neuron 30:369–383
Biervert C, Schroeder BC, Kubisch C, Berkovic SF, Propping P, Jentsch TJ, Steinlein OK (1998) A potassium channel mutation in neonatal human epilepsy. Science 279:403–406
Bjartmar C, Yin X, Trapp BD (1999) Axonal pathology in myelin disorders. J Neurocytol 28:383–395
Bostock H, Sharief M, Reid G, Murray N (1995) Axonal ion channel dysfunction in amyotrophic lateral sclerosis. Brain 118:217–225
Boyle ME, Berglund EO, Murai KK, Weber L, Peles E, Ranscht B (2001) Contactin orchestrates assembly of the septate-like junctions at the paranode in myelinated peripheral nerve. Neuron 30:385–397
Brohawn SG, Wang W, Handler A, Campbell EB, Schwarz JR, MacKinnon R (2019) The mechanosensitive ion channel TRAAK is localized to the mammalian node of Ranvier. Elife 8:e50403
Brun A, Englund E (1986) A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study. Ann Neurol 19:253–262
Büki A, Siman R, Trojanowski JQ, Povlishock JT (1999) The role of calpain-mediated spectrin proteolysis in traumatically induced axonal injury. J Neuropathol Exp Neurol 58:365–375
Buttermore ED, Dupree JL, Cheng J, An X, Tessarollo L, Bhat MA (2011) The cytoskeletal adaptor protein band 4.1 B is required for the maintenance of paranodal axoglial septate junctions in myelinated axons. J Neurosci 31:8013–8024
Calvo M, Richards N, Schmid AB, Barroso A, Zhu L, Ivulic D, Zhu N, Anwandter P, Bhat MA, McMahon SB (2016) Altered potassium channel distribution and composition in myelinated axons suppresses hyperexcitability following injury. Elife 5:e12661
Canali G, Goutebroze L (2018) CNTNAP2 heterozygous missense variants: risk factors for autism spectrum disorder and/or other pathologies? J Exp Neurosci 12:1179069518809666
Carvalho Md (2000) Pathophysiological significance of fasciculations in the early diagnosis of ALS. Amyotroph Lateral Scler Other Motor Neuron Disord 1:S43–S46
Charles P, Tait S, Faivre-Sarrailh C, Barbin G, Gunn-Moore F, Denisenko-Nehrbass N, Guennoc A-M, Girault J-A, Brophy PJ, Lubetzki C (2002) Neurofascin is a glial receptor for the paranodin/Caspr-contactin axonal complex at the axoglial junction. Curr Biol 12:217–220
Chatzopoulou E, Miguez A, Savvaki M, Levasseur G, Muzerelle A, Muriel M-P, Goureau O, Watanabe K, Goutebroze L, Gaspar P (2008) Structural requirement of TAG-1 for retinal ganglion cell axons and myelin in the mouse optic nerve. J Neurosci 28:7624–7636
Chen J-F, Liu K, Hu B, Li R-R, Xin W, Chen H, Wang F, Chen L, Li R-X, Ren S-Y (2021) Enhancing myelin renewal reverses cognitive dysfunction in a murine model of Alzheimer’s disease. Neuron 109(2292–2307):e2295
Ching W, Zanazzi G, Levinson SR, Salzer JL (1999) Clustering of neuronal sodium channels requires contact with myelinating Schwann cells. J Neurocytol 28:295–301
Cole SL, Vassar R (2007) The Alzheimer’s disease β-secretase enzyme, BACE1. Mol Neurodegener 2:1–25
Cortese A, Lombardi R, Briani C, Callegari I, Benedetti L, Manganelli F, Luigetti M, Ferrari S, Clerici AM, Marfia GA (2020) Antibodies to neurofascin, contactin-1, and contactin-associated protein 1 in CIDP: Clinical relevance of IgG isotype. Neurol Neuroimmunol Neuroinflamm 7:639
Craner MJ, Newcombe J, Black JA, Hartle C, Cuzner ML, Waxman SG (2004) Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1. 2 and Nav1. 6 sodium channels and Na+/Ca2+ exchanger. Proc Natl Acad Sci 101:8168–8173
Dashtban S, Haj-Nasrolah-Fard F, Kosari Z, Ghamari R, Forouzesh F, Alizadeh F (2022) ANK3 and ZNF804A intronic variants increase risk of schizophrenia in Iranian population: An association study. Gene Reports:101511
Davenport ND, Lim KO, Armstrong MT, Sponheim SR (2012) Diffuse and spatially variable white matter disruptions are associated with blast-related mild traumatic brain injury. Neuroimage 59:2017–2024
Davis KL, Stewart DG, Friedman JI, Buchsbaum M, Harvey PD, Hof PR, Buxbaum J, Haroutunian V (2003) White matter changes in schizophrenia: evidence for myelin-related dysfunction. Arch Gen Psychiatry 60:443–456
Delmont E, Manso C, Querol L, Cortese A, Berardinelli A, Lozza A, Belghazi M, Malissart P, Labauge P, Taieb G (2017) Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy. Brain 140:1851–1858
Derfuss T, Linington C, Hohlfeld R, Meinl E (2010) Axo-glial antigens as targets in multiple sclerosis: implications for axonal and grey matter injury. J Mol Med 88:753–761
Derfuss T, Parikh K, Velhin S, Braun M, Mathey E, Krumbholz M, Kümpfel T, Moldenhauer A, Rader C, Sonderegger P (2009) Contactin-2/TAG-1-directed autoimmunity is identified in multiple sclerosis patients and mediates gray matter pathology in animals. Proc Natl Acad Sci 106:8302–8307
Desai MK, Sudol KL, Janelsins MC, Mastrangelo MA, Frazer ME, Bowers WJ (2009) Triple-transgenic Alzheimer’s disease mice exhibit region-specific abnormalities in brain myelination patterns prior to appearance of amyloid and tau pathology. Glia 57:54–65
Desai MK, Mastrangelo MA, Ryan DA, Sudol KL, Narrow WC, Bowers WJ (2010) Early oligodendrocyte/myelin pathology in Alzheimer’s disease mice constitutes a novel therapeutic target. Am J Pathol 177:1422–1435
Devaux JJ, Odaka M, Yuki N (2012) Nodal proteins are target antigens in Guillain-Barré syndrome. J Peripher Nerv Syst 17:62–71
Doppler K, Appeltshauser L, Wilhelmi K, Villmann C, Dib-Hajj SD, Waxman SG, Mäurer M, Weishaupt A, Sommer C (2015) Destruction of paranodal architecture in inflammatory neuropathy with anti-contactin-1 autoantibodies. J Neurol Neurosurg Psychiatry 86:720–728
Doppler K, Appeltshauser L, Villmann C, Martin C, Peles E, Krämer HH, Haarmann A, Buttmann M, Sommer C (2016) Auto-antibodies to contactin-associated protein 1 (Caspr) in two patients with painful inflammatory neuropathy. Brain 139:2617–2630
Dugandzija-Novakovic S, Koszowski AG, Levinson SR, Shrager P (1995) Clustering of Na+ channels and node of Ranvier formation in remyelinating axons. J Neurosci 15:492–503
Einheber S, Meng X, Rubin M, Lam I, Mohandas N, An X, Shrager P, Kissil J, Maurel P, Salzer JL (2013) The 4.1 B cytoskeletal protein regulates the domain organization and sheath thickness of myelinated axons. Glia 61:240–253
Escayg A, Goldin AL (2010) Sodium channel SCN1A and epilepsy: mutations and mechanisms. Epilepsia 51:1650–1658
Eshed Y, Feinberg K, Carey DJ, Peles E (2007) Secreted gliomedin is a perinodal matrix component of peripheral nerves. J Cell Biol 177:551–562
Estacion M, O’Brien JE, Conravey A, Hammer MF, Waxman SG, Dib-Hajj SD, Meisler MH (2014) A novel de novo mutation of SCN8A (Nav1. 6) with enhanced channel activation in a child with epileptic encephalopathy. Neurobiol Dis 69:117–123
Faivre-Sarrailh C (2020) Molecular organization and function of vertebrate septate-like junctions. Biochimica et Biophysica Acta (BBA)-Biomembranes 1862:183211
Faivre-Sarrailh C, Devaux JJ (2013) Neuro-glial interactions at the nodes of Ranvier: implication in health and diseases. Front Cell Neurosci 7:196
Fan C, Jin H, Hao H, Gao F, Sun Y, Lu Y, Liu Y, Lv P, Cui W, Teng Y (2017) Anti-ganglioside antibodies in Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy in Chinese patients. Muscle Nerve 55:470–475
Feinberg K, Eshed-Eisenbach Y, Frechter S, Amor V, Salomon D, Sabanay H, Dupree JL, Grumet M, Brophy PJ, Shrager P (2010) A glial signal consisting of gliomedin and NrCAM clusters axonal Na+ channels during the formation of nodes of Ranvier. Neuron 65:490–502
Ferraiuolo L, Meyer K, Sherwood TW, Vick J, Likhite S, Frakes A, Miranda CJ, Braun L, Heath PR, Pineda R (2016) Oligodendrocytes contribute to motor neuron death in ALS via SOD1-dependent mechanism. Proc Natl Acad Sci 113:E6496–E6505
Fischer LR, Culver DG, Tennant P, Davis AA, Wang M, Castellano-Sanchez A, Khan J, Polak MA, Glass JD (2004) Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol 185:232–240
Fledrich R, Kungl T, Nave K-A, Stassart RM (2019) Axo-glial interdependence in peripheral nerve development. Development 146:dev151704
Fornari E, Maeder P, Meuli R, Ghika J, Knyazeva MG (2012) Demyelination of superficial white matter in early Alzheimer's disease: a magnetization transfer imaging study. Neurobiology of aging 33:428. e427–428. e419
Freeman SA, Desmazières A, Fricker D, Lubetzki C, Sol-Foulon N (2016) Mechanisms of sodium channel clustering and its influence on axonal impulse conduction. Cell Mol Life Sci 73:723–735
Freeman SA, Desmazières A, Simonnet J, Gatta M, Pfeiffer F, Aigrot MS, Rappeneau Q, Guerreiro S, Michel PP, Yanagawa Y (2015) Acceleration of conduction velocity linked to clustering of nodal components precedes myelination. Proc Natl Acad Sci 112:E321–E328
Fu Y, Cheng J-X, Frederick TJ, Goings GE, Miller SD, Huff TB (2011) Paranodal myelin retraction in relapsing experimental autoimmune encephalomyelitis visualized by coherent anti-Stokes Raman scattering microscopy. J Biomed Opt 16:106006
Gallego-Delgado P, James R, Browne E, Meng J, Umashankar S, Tan L, Picon C, Mazarakis ND, Faisal AA, Howell OW (2020) Neuroinflammation in the normal-appearing white matter (NAWM) of the multiple sclerosis brain causes abnormalities at the nodes of Ranvier. PLoS Biol 18:e3001008
Giovannelli I, Higginbottom A, Kirby J, Azzouz M, Shaw PJ (2022) Prospects for gene replacement therapies in amyotrophic lateral sclerosis. Nat Rev Neurol:1–14
Gold BT, Johnson NF, Powell DK, Smith CD (2012) White matter integrity and vulnerability to Alzheimer's disease: preliminary findings and future directions. Biochim Biophys Acta Mol Basis Dis 1822:416–422
Griffin J, Li C, Macko C, Ho T, Hsieh S-T, Xue P, Wang F, Cornblath D, McKhann G, Asbury A (1996) Early nodal changes in the acute motor axonal neuropathy pattern of the Guillain-Barré syndrome. J Neurocytol 25:33–51
Guimaraes J, Freire M, Lima R, Souza-Rodrigues R, Costa A, dos Santos C, Picanço-Diniz C, Gomes-Leal W (2009) Mechanisms of secondary degeneration in the central nervous system during acute neural disorders and white matter damage. Rev Neurol 48:304–310
Guo X, Zhang Y, Du J, Yang H, Ma Y, Li J, Yan M, Jin T, Liu X (2016) Association analysis of ANK3 gene variants with schizophrenia in a northern Chinese Han population. Oncotarget 7:85888
Heurteaux C, Guy N, Laigle C, Blondeau N, Duprat F, Mazzuca M, Lang-Lazdunski L, Widmann C, Zanzouri M, Romey G (2004) TREK-1, a K+ channel involved in neuroprotection and general anesthesia. EMBO J 23:2684–2695
Horsburgh K, Reimer MM, Holland P, Chen G, Scullion G, Fowler JH (2011) Axon–glial disruption: the link between vascular disease and Alzheimer’s disease? Biochem Soc Trans 39:881–885
Howell O, Palser A, Polito A, Melrose S, Zonta B, Scheiermann C, Vora A, Brophy P, Reynolds R (2006) Disruption of neurofascin localization reveals early changes preceding demyelination and remyelination in multiple sclerosis. Brain 129:3173–3185
Howell OW, Rundle JL, Garg A, Komada M, Brophy PJ, Reynolds R (2010) Activated microglia mediate axoglial disruption that contributes to axonal injury in multiple sclerosis. J Neuropathol Exp Neurol 69:1017–1033
Howells J, Matamala JM, Park SB, Garg N, Vucic S, Bostock H, Burke D, Kiernan MC (2018) In vivo evidence for reduced ion channel expression in motor axons of patients with amyotrophic lateral sclerosis. J Physiol 596:5379–5396
Hu J, Chen L, Huang X, Wu K, Ding S, Wang W, Wang B, Smith C, Ren C, Ni H (2019) Calpain inhibitor MDL28170 improves the transplantation-mediated therapeutic effect of bone marrow-derived mesenchymal stem cells following traumatic brain injury. Stem Cell Res Ther 10:1–13
Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, Yan R (2006) Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci 9:1520–1525
Huang CY-M, Zhang C, Zollinger DR, Leterrier C, Rasband MN (2017) An αII spectrin-based cytoskeleton protects large-diameter myelinated axons from degeneration. J Neurosci 37:11323–11334
Iwai Y, Shibuya K, Misawa S, Sekiguchi Y, Watanabe K, Amino H, Kuwabara S (2016) Axonal dysfunction precedes motor neuronal death in amyotrophic lateral sclerosis. PLoS ONE 11:e0158596
Iwata A, Stys PK, Wolf JA, Chen X-H, Taylor AG, Meaney DF, Smith DH (2004) Traumatic axonal injury induces proteolytic cleavage of the voltage-gated sodium channels modulated by tetrodotoxin and protease inhibitors. J Neurosci 24:4605–4613
Jarjour AA, Velichkova AN, Boyd A, Lord KM, Torsney C, Henderson DJ, ffrench-Constant C, (2020) The formation of paranodal spirals at the ends of CNS myelin sheaths requires the planar polarity protein Vangl2. Glia 68:1840–1858
Johnson VE, Stewart W, Smith DH (2013) Axonal pathology in traumatic brain injury. Exp Neurol 246:35–43
Kanda H, Ling J, Tonomura S, Noguchi K, Matalon S, Gu JG (2019) TREK-1 and TRAAK are principal K+ channels at the nodes of Ranvier for rapid action potential conduction on mammalian myelinated afferent nerves. Neuron 104(960–971):e967
Kastriti ME, Sargiannidou I, Kleopa KA, Karagogeos D (2015) Differential modulation of the juxtaparanodal complex in multiple sclerosis. Mol Cell Neurosci 67:93–103
Kelly S, Jahanshad N, Zalesky A, Kochunov P, Agartz I, Alloza C, Andreassen O, Arango C, Banaj N, Bouix S (2018) Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group. Mol Psychiatry 23:1261–1269
Kim DY, Carey BW, Wang H, Ingano LA, Binshtok AM, Wertz MH, Pettingell WH, He P, Lee VM-Y, Woolf CJ (2007) BACE1 regulates voltage-gated sodium channels and neuronal activity. Nat Cell Biol 9:755–764
Kira J-i, Yamasaki R, Ogata H (2019) Anti-neurofascin autoantibody and demyelination. Neurochem Int 130:104360
Kloth K, Denecke J, Hempel M, Johannsen J, Strom TM, Kubisch C, Lessel D (2017) First de novo ANK3 nonsense mutation in a boy with intellectual disability, speech impairment and autistic features. Eur J Med Genet 60:494–498
Kochunov P, Huang J, Chen S, Li Y, Tan S, Fan F, Feng W, Wang Y, Rowland LM, Savransky A (2019) White matter in schizophrenia treatment resistance. Am J Psychiatry 176:829–838
Koga M (2018) autoantibodies in chronic inflammatory demyelinating polyneuropathy. Brain and Nerve = Shinkei Kenkyu no Shinpo 70:395–403
Koike H, Kadoya M, Kaida K-i, Ikeda S, Kawagashira Y, Iijima M, Kato D, Ogata H, Yamasaki R, Matsukawa N (2017) Paranodal dissection in chronic inflammatory demyelinating polyneuropathy with anti-neurofascin-155 and anti-contactin-1 antibodies. J Neurol Neurosurg Psychiatry 88:465–473
Komada M, Soriano P (2002) βIV-spectrin regulates sodium channel clustering through ankyrin-G at axon initial segments and nodes of Ranvier. J Cell Biol 156:337–348
Komatsu H, Takeuchi H, Kikuchi Y, Ono C, Yu Z, Iizuka K, Takano Y, Kakuto Y, Funakoshi S, Ono T (2020) Ethnicity-dependent effects of schizophrenia risk variants of the OLIG2 gene on OLIG2 transcription and white matter integrity. Schizophr Bull 46:1619–1628
Konrad A, Winterer G (2008) Disturbed structural connectivity in schizophrenia—primary factor in pathology or epiphenomenon? Schizophr Bull 34:72–92
Krumbholz M, Derfuss T, Hohlfeld R, Meinl E (2012) B cells and antibodies in multiple sclerosis pathogenesis and therapy. Nat Rev Neurol 8:613–623
Kuwabara S (2004) Guillain-barré syndrome. Drugs 64:597–610
Kwok J, Warren P, Fawcett J (2012) Chondroitin sulfate: a key molecule in the brain matrix. Int J Biochem Cell Biol 44:582–586
Lassmann H, Van Horssen J, Mahad D (2012) Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol 8:647–656
Li S, Wang X, Ma Q-H, Yang W-l, Zhang X-G, Dawe GS, Xiao Z-C (2016) Amyloid precursor protein modulates Nav1. 6 sodium channel currents through a Go-coupled JNK pathway. Sci Rep 6:1–16
Lindner M, Ng JKM, Hochmeister S, Meinl E, Linington C (2013) Neurofascin 186 specific autoantibodies induce axonal injury and exacerbate disease severity in experimental autoimmune encephalomyelitis. Exp Neurol 247:259–266
Lonigro A, Devaux JJ (2009) Disruption of neurofascin and gliomedin at nodes of Ranvier precedes demyelination in experimental allergic neuritis. Brain 132:260–273
Lu Z, Reddy MS, Liu J, Kalichava A, Liu J, Zhang L, Chen F, Wang Y, Holthauzen LMF, White MA (2016) Molecular architecture of contactin-associated protein-like 2 (CNTNAP2) and its interaction with contactin 2 (CNTN2). J Biol Chem 291:24133–24147
Maglemose R, Hedegaard A, Lehnhoff J, Dimintiyanova KP, Moldovan M, Grøndahl L, Meehan CF (2017) Potassium channel abnormalities are consistent with early axon degeneration of motor axons in the G127X SOD1 mouse model of amyotrophic lateral sclerosis. Exp Neurol 292:154–167
Malek E, Salameh J (2019) Guillain–Barre Syndrome. In: Seminars in neurology, pp 589–595: Thieme Medical Publishers
Manso C, Querol L, Mekaouche M, Illa I, Devaux JJ (2016) Contactin-1 IgG4 antibodies cause paranode dismantling and conduction defects. Brain 139:1700–1712
Manville RW, Abbott GW (2021) The Amyloid Precursor Protein C99 Fragment Modulates Voltage-Gated Potassium Channels. Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology 55:157
Marin MA, Ziburkus J, Jankowsky J, Rasband MN (2016) Amyloid-β plaques disrupt axon initial segments. Exp Neurol 281:93–98
Martin MS, Tang B, Papale LA, Yu FH, Catterall WA, Escayg A (2007) The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy. Hum Mol Genet 16:2892–2899
Mathey EK, Derfuss T, Storch MK, Williams KR, Hales K, Woolley DR, Al-Hayani A, Davies SN, Rasband MN, Olsson T (2007) Neurofascin as a novel target for autoantibody-mediated axonal injury. J Exp Med 204:2363–2372
Mathis C, Denisenko-Nehrbass N, Girault J-A, Borrelli E (2001) Essential role of oligodendrocytes in the formation and maintenance of central nervous system nodal regions
McGonigal R, Rowan EG, Greenshields KN, Halstead SK, Humphreys PD, Rother RP, Furukawa K, Willison HJ (2010) Anti-GD1a antibodies activate complement and calpain to injure distal motor nodes of Ranvier in mice. Brain 133:1944–1960
Melendez-Vasquez C, Carey DJ, Zanazzi G, Reizes O, Maurel P, Salzer JL (2005) Differential expression of proteoglycans at central and peripheral nodes of Ranvier. Glia 52:301–308
Mogyoros I, Kiernan MC, Burke D, Bostock H (1998) Strength-duration properties of sensory and motor axons in amyotrophic lateral sclerosis. Brain: J Neurol 121:851–859
Mondello S, Robicsek SA, Gabrielli A, Brophy GM, Papa L, Tepas J III, Robertson C, Buki A, Scharf D, Jixiang M (2010) αII-spectrin breakdown products (SBDPs): diagnosis and outcome in severe traumatic brain injury patients. J Neurotrauma 27:1203–1213
Mori T, Ohnishi T, Hashimoto R, Nemoto K, Moriguchi Y, Noguchi H, Nakabayashi T, Hori H, Harada S, Saitoh O (2007) Progressive changes of white matter integrity in schizophrenia revealed by diffusion tensor imaging. Psychiatry Research: Neuroimaging 154:133–145
Moshé SL, Perucca E, Ryvlin P, Tomson T (2015) Epilepsy: new advances. The Lancet 385:884–898
Mu J, Li M, Wang T, Li X, Bai M, Zhang G, Kong J (2019) Myelin damage in diffuse axonal injury. Front Neurosci 13:217
Nazeri A, Chakravarty MM, Felsky D, Lobaugh NJ, Rajji TK, Mulsant BH, Voineskos AN (2013) Alterations of superficial white matter in schizophrenia and relationship to cognitive performance. Neuropsychopharmacology 38:1954–1962
Ng JKM, Malotka J, Kawakami N, Derfuss T, Khademi M, Olsson T, Linington C, Odaka M, Tackenberg B, Prüss H (2012) Neurofascin as a target for autoantibodies in peripheral neuropathies. Neurology 79:2241–2248
Nie F, Wang X, Zhao P, Yang H, Zhu W, Zhao Y, Chen B, Valenzuela RK, Zhang R, Gallitano AL (2015) Genetic analysis of SNPs in CACNA1C and ANK3 gene with schizophrenia: A comprehensive meta-analysis. Am J Med Genet B Neuropsychiatr Genet 168:637–648
Nonneman A, Robberecht W, Den Bosch LV (2014) The role of oligodendroglial dysfunction in amyotrophic lateral sclerosis. Neurodegenerative Disease Management 4:223–239
Nyati KK, Nyati R (2013) Role of Campylobacter jejuni infection in the pathogenesis of Guillain-Barré syndrome: an update. BioMed Res Int
Oliva M, Berkovic SF, Petrou S (2012) Sodium channels and the neurobiology of epilepsy. Epilepsia 53:1849–1859
Ouyang H, Sun W, Fu Y, Li J, Cheng J-X, Nauman E, Shi R (2010) Compression induces acute demyelination and potassium channel exposure in spinal cord. J Neurotrauma 27:1109–1120
Papale LA, Beyer B, Jones JM, Sharkey LM, Tufik S, Epstein M, Letts VA, Meisler MH, Frankel WN, Escayg A (2009) Heterozygous mutations of the voltage-gated sodium channel SCN8A are associated with spike-wave discharges and absence epilepsy in mice. Hum Mol Genet 18:1633–1641
Peles E, Salzer JL (2000) Molecular domains of myelinated axons. Curr Opin Neurobiol 10:558–565
Peñagarikano O, Geschwind DH (2012) What does CNTNAP2 reveal about autism spectrum disorder? Trends Mol Med 18:156–163
Peñagarikano O, Abrahams BS, Herman EI, Winden KD, Gdalyahu A, Dong H, Sonnenblick LI, Gruver R, Almajano J, Bragin A (2011) Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 147:235–246
Philips T, Bento-Abreu A, Nonneman A, Haeck W, Staats K, Geelen V, Hersmus N, Küsters B, Van Den Bosch L, Van Damme P (2013) Oligodendrocyte dysfunction in the pathogenesis of amyotrophic lateral sclerosis. Brain 136:471–482
Poliak S, Salomon D, Elhanany H, Sabanay H, Kiernan B, Pevny L, Stewart CL, Xu X, Chiu S-Y, Shrager P (2003) Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1. J Cell Biol 162:1149–1160
Poot M (2015) Connecting the CNTNAP2 networks with neurodevelopmental disorders. Molecular Syndromology 6:7–22
Posmantur R, Kampfl A, Siman R, Liu S, Zhao X, Clifton G, Hayes R (1997) A calpain inhibitor attenuates cortical cytoskeletal protein loss after experimental traumatic brain injury in the rat. Neuroscience 77:875–888
Rafałowska J, Dziewulska D (1996) White matter injury in amyotrophic lateral sclerosis (ALS). Folia Neuropathol 34:87–91
Rasband MN, Peles E (2021) Mechanisms of node of Ranvier assembly. Nat Rev Neurosci 22:7–20
Rasband MN, Peles E, Trimmer JS, Levinson SR, Lux SE, Shrager P (1999) Dependence of nodal sodium channel clustering on paranodal axoglial contact in the developing CNS. J Neurosci 19:7516–7528
Reeves TM, Greer JE, Vanderveer AS, Phillips LL (2010) Proteolysis of submembrane cytoskeletal proteins Ankyrin-G and αII-Spectrin Following diffuse brain Injury: a role in white matter vulnerability at nodes of ranvier. Brain Pathol 20:1055–1068
Rios JC, Melendez-Vasquez CV, Einheber S, Lustig M, Grumet M, Hemperly J, Peles E, Salzer JL (2000) Contactin-associated protein (Caspr) and contactin form a complex that is targeted to the paranodal junctions during myelination. J Neurosci 20:8354–8364
Rios JC, Rubin M, Martin MS, Downey RT, Einheber S, Rosenbluth J, Levinson SR, Bhat M, Salzer JL (2003) Paranodal interactions regulate expression of sodium channel subtypes and provide a diffusion barrier for the node of Ranvier. J Neurosci 23:7001–7011
Ronzano R, Roux T, Thetiot M, Aigrot M, Richard L, Lejeune F, Mazuir E, Vallat J, Lubetzki C, Desmazières A (2021) Microglia-neuron interaction at nodes of Ranvier depends on neuronal activity through potassium release and contributes to remyelination. Nat Commun 12:1–18
Rosenfeld JA, Xiao R, Bekheirnia MR, Kanani F, Parker MJ, Koenig MK, van Haeringen A, Ruivenkamp C, Rosmaninho-Salgado J, Almeida PM (2021) Heterozygous variants in SPTBN1 cause intellectual disability and autism. Am J Med Genet A 185:2037–2045
Roussos P, Haroutunian V (2014a) Schizophrenia: susceptibility genes and oligodendroglial and myelin related abnormalities. Front Cell Neurosci 8:5
Roussos P, Haroutunian V (2014b) Schizophrenia: susceptibility genes and oligodendroglial and myelin related abnormalities. Front Cell Neurosci 8
Roussos P, Katsel P, Davis KL, Bitsios P, Giakoumaki SG, Jogia J, Rozsnyai K, Collier D, Frangou S, Siever LJ (2012) Molecular and genetic evidence for abnormalities in the nodes of Ranvier in schizophrenia. Arch Gen Psychiatry 69:7–15
Ruitenberg A, Den Heijer T, Bakker SL, Van Swieten JC, Koudstaal PJ, Hofman A, Breteler MM (2005) Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society 57:789–794
Saatman KE, Bozyczko-Coyne D, Marcy V, Siman R, McIntosh TK (1996) Prolonged calpain-mediated spectrin breakdown occurs regionally following experimental brain injury in the rat. J Neuropathol Exp Neurol 55:850–860
Sach M, Winkler G, Glauche V, Liepert J, Heimbach B, Koch MA, BuÈchel C, Weiller C (2004) Diffusion tensor MRI of early upper motor neuron involvement in amyotrophic lateral sclerosis. Brain 127:340–350
Saeedimasine M, Montanino A, Kleiven S, Villa A (2021) Elucidating axonal injuries through molecular modelling of myelin sheaths and nodes of Ranvier. Front Mol Biosci 8:379
Sahranavard S, Khoramjouy M, Khakpash M, Askari SA, Faizi M, Mosaddegh M (2022) Hydroethanolic extract of Lavandula angustifolia ameliorates vincristine-induced peripheral neuropathy in rats. Res Pharm Sci 17:265
Saito F, Moore SA, Barresi R, Henry MD, Messing A, Ross-Barta SE, Cohn RD, Williamson RA, Sluka KA, Sherman DL (2003) Unique role of dystroglycan in peripheral nerve myelination, nodal structure, and sodium channel stabilization. Neuron 38:747–758
Salzer JL, Brophy PJ, Peles E (2008) Molecular domains of myelinated axons in the peripheral nervous system. Glia 56:1532–1540
Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL (2012) De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485:237–241
Santoro M, Thomas FP, Fink ME, Lange DJ, Uncini A, Wadia NH, Latov N, Hays AP (1990) IgM deposits at nodes of Ranvier in a patient with amyotrophic lateral sclerosis, anti-GM1 antibodies, and multifocal motor conduction block. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society 28:373–377
Sarro L, Agosta F, Canu E, Riva N, Prelle A, Copetti M, Riccitelli G, Comi G, Filippi M (2011) Cognitive functions and white matter tract damage in amyotrophic lateral sclerosis: a diffusion tensor tractography study. Am J Neuroradiol 32:1866–1872
Savvaki M, Theodorakis K, Zoupi L, Stamatakis A, Tivodar S, Kyriacou K, Stylianopoulou F, Karagogeos D (2010) The expression of TAG-1 in glial cells is sufficient for the formation of the juxtaparanodal complex and the phenotypic rescue of tag-1 homozygous mutants in the CNS. J Neurosci 30:13943–13954
Savvaki M, Panagiotaropoulos T, Stamatakis A, Sargiannidou I, Karatzioula P, Watanabe K, Stylianopoulou F, Karagogeos D, Kleopa KA (2008) Impairment of learning and memory in TAG-1 deficient mice associated with shorter CNS internodes and disrupted juxtaparanodes. Mol Cell Neurosci 39:478–490
Schafer DP, Custer AW, Shrager P, Rasband MN (2006) Early events in node of Ranvier formation during myelination and remyelination in the PNS. Neuron Glia Biol 2:69–79
Schafer DP, Jha S, Liu F, Akella T, McCullough LD, Rasband MN (2009) Disruption of the axon initial segment cytoskeleton is a new mechanism for neuronal injury. J Neurosci 29:13242–13254
Schwarz JR (2021) Function of K2P channels in the mammalian node of Ranvier. J Physiol 599:4427–4439
Shahrizaila N, Lehmann HC, Kuwabara S (2021) Guillain-Barré syndrome. The Lancet 397:1214–1228
Shi L, Zhang X, Golhar R, Otieno FG, He M, Hou C, Kim C, Keating B, Lyon GJ, Wang K (2013) Whole-genome sequencing in an autism multiplex family. Molecular Autism 4:1–15
Shibuya K, Misawa S, Arai K, Nakata M, Kanai K, Yoshiyama Y, Ito K, Isose S, Noto Y-i, Nasu S (2011) Markedly reduced axonal potassium channel expression in human sporadic amyotrophic lateral sclerosis: an immunohistochemical study. Exp Neurol 232:149–153
Simons M, Trotter J (2007) Wrapping it up: the cell biology of myelination. Curr Opin Neurobiol 17:533–540
Singh NA, Westenskow P, Charlier C, Pappas C, Leslie J, Dillon J, Anderson VE, Sanguinetti MC, Leppert MF (2003) KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. Brain 126:2726–2737
Singh NA, Charlier C, Stauffer D, DuPont BR, Leach RJ, Melis R, Ronen GM, Bjerre I, Quattlebaum T, Murphy JV (1998) A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet 18:25–29
Smart SL, Lopantsev V, Zhang C, Robbins CA, Wang H, Chiu S, Schwartzkroin PA, Messing A, Tempel BL (1998) Deletion of the Kv1. 1 potassium channel causes epilepsy in mice. Neuron 20:809–819
Stich O, Perera S, Berger B, Jarius S, Wildemann B, Baumgartner A, Rauer S (2016) Prevalence of neurofascin-155 antibodies in patients with multiple sclerosis. J Neurol Sci 364:29–32
Strauss KA, Puffenberger EG, Huentelman MJ, Gottlieb S, Dobrin SE, Parod JM, Stephan DA, Morton DH (2006) Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med 354:1370–1377
Susuki K (2013) Node of Ranvier disruption as a cause of neurological diseases. ASN neuro 5:AN20130025
Susuki K (2016) Node of Ranvier disruption in Guillain-Barré syndrome. Clinical and Experimental Neuroimmunology 7:324–329
Susuki K, Rasband MN (2008) Molecular mechanisms of node of Ranvier formation. Curr Opin Cell Biol 20:616–623
Susuki K, Yuki N, Schafer DP, Hirata K, Zhang G, Funakoshi K, Rasband MN (2012) Dysfunction of nodes of Ranvier: a mechanism for anti-ganglioside antibody-mediated neuropathies. Exp Neurol 233:534–542
Susuki K, Rasband MN, Tohyama K, Koibuchi K, Okamoto S, Funakoshi K, Hirata K, Baba H, Yuki N (2007) Anti-GM1 antibodies cause complement-mediated disruption of sodium channel clusters in peripheral motor nerve fibers. J Neurosci 27:3956–3967
Susuki K, Chang K-J, Zollinger DR, Liu Y, Ogawa Y, Eshed-Eisenbach Y, Dours-Zimmermann MT, Oses-Prieto JA, Burlingame AL, Seidenbecher CI (2013) Three mechanisms assemble central nervous system nodes of Ranvier. Neuron 78:469–482
Susuki K, Zollinger DR, Chang K-J, Zhang C, Huang CY-M, Tsai C-R, Galiano MR, Liu Y, Benusa SD, Yermakov LM (2018) Glial βII spectrin contributes to paranode formation and maintenance. J Neurosci 38:6063–6075
Tang L, Huang Q, Qin Z, Tang X (2021) Distinguish CIDP with autoantibody from that without autoantibody: pathogenesis, histopathology, and clinical features. J Neurol 268:2757–2768
Tonomura S, Gu JG (2022) Role of voltage-gated K+ channels and K2P channels in intrinsic electrophysiological properties and saltatory conduction at nodes of Ranvier of rat lumbar spinal ventral nerves. J Neurosci 42:4980–4994
Traiffort E, Morisset-Lopez S, Moussaed M, Zahaf A (2021) Defective Oligodendroglial Lineage and Demyelination in Amyotrophic Lateral Sclerosis. Int J Mol Sci 22:3426
Trapp BD, Kidd GJ (2000) Axo-glial septate junctions: the maestro of nodal formation and myelination? J Cell Biol 150:F97–F100
Uranova NA, Vikhreva OV, Rachmanova VI, Orlovskaya DD (2011) Ultrastructural alterations of myelinated fibers and oligodendrocytes in the prefrontal cortex in schizophrenia: a postmortem morphometric study. Schizophrenia Res Treatment
Uranova NA, Vikhreva OV, Rakhmanova VI, Orlovskaya DD (2020) Dystrophy of oligodendrocytes and adjacent microglia in prefrontal gray matter in schizophrenia. Front Psych 11:204
Uranova NA, Vostrikov VM, Vikhreva OV, Zimina IS, Kolomeets NS, Orlovskaya DD (2007) The role of oligodendrocyte pathology in schizophrenia. Int J Neuropsychopharmacol 10:537–545
Vabnick I, Novaković SD, Levinson SR, Schachner M, Shrager P (1996) The clustering of axonal sodium channels during development of the peripheral nervous system. J Neurosci 16:4914–4922
Valdés-Tovar M, Rodríguez-Ramírez AM, Rodríguez-Cárdenas L, Sotelo-Ramírez CE, Camarena B, Sanabrais-Jiménez MA, Solís-Chagoyán H, Argueta J, López-Riquelme GO (2022) Insights into myelin dysfunction in schizophrenia and bipolar disorder. World J Psychiatry 12:264
Vallat J-M, Mathis S, Magy L, Bounolleau P, Skarzynski M, Heitzmann A, Manso C, Devaux J, Uncini A (2018) Subacute nodopathy with conduction blocks and anti-neurofascin 140/186 antibodies: An ultrastructural study. Brain
Veeramah KR, O’Brien JE, Meisler MH, Cheng X, Dib-Hajj SD, Waxman SG, Talwar D, Girirajan S, Eichler EE, Restifo LL (2012) De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. The American Journal of Human Genetics 90:502–510
Vikhreva O, Rakhmanova V, Orlovskaya D, Uranova N (2016) Ultrastructural alterations of oligodendrocytes in prefrontal white matter in schizophrenia: a post-mortem morphometric study. Schizophr Res 177:28–36
Vitolo E, Tatu MK, Pignolo C, Cauda F, Costa T, Zennaro A (2017) White matter and schizophrenia: a meta-analysis of voxel-based morphometry and diffusion tensor imaging studies. Psychiatry Research: Neuroimaging 270:8–21
Voineskos AN, de Luca V, Bulgin NL, van Adrichem Q, Shaikh S, Lang DJ, Honer WG, Kennedy JL (2008) A family-based association study of the myelin-associated glycoprotein and 2′, 3′-cyclic nucleotide 3′-phosphodiesterase genes with schizophrenia. Psychiatr Genet 18:143–146
Vucic S, Lin CS-Y, Cheah BC, Murray J, Menon P, Krishnan AV, Kiernan MC (2013) Riluzole exerts central and peripheral modulating effects in amyotrophic lateral sclerosis. Brain 136:1361–1370
Vural A, Doppler K, Meinl E (2018) Autoantibodies against the node of Ranvier in seropositive chronic inflammatory demyelinating polyneuropathy: diagnostic, pathogenic, and therapeutic relevance. Front Immunol 9:1029
Wang C-C, Ortiz-González XR, Yum SW, Gill SM, White A, Kelter E, Seaver LH, Lee S, Wiley G, Gaffney PM (2018) βIV spectrinopathies cause profound intellectual disability, congenital hypotonia, and motor axonal neuropathy. The American Journal of Human Genetics 102:1158–1168
Wang X, Zhang X-G, Zhou T-T, Li N, Jang C-Y, Xiao Z-C, Ma Q-H, Li S (2016) Elevated neuronal excitability due to modulation of the voltage-gated Sodium Channel Nav1. 6 by Aβ1− 42. Front Neurosci 10:94
Waxman SG (2006) Axonal conduction and injury in multiple sclerosis: the role of sodium channels. Nat Rev Neurosci 7:932–941
Weiss L, Escayg A, Kearney J, Trudeau M, MacDonald B, Mori M, Reichert J, Buxbaum J, Meisler M (2003) Sodium channels SCN1A, SCN2A and SCN3A in familial autism. Mol Psychiatry 8:186–194
Wong H-K, Sakurai T, Oyama F, Kaneko K, Wada K, Miyazaki H, Kurosawa M, De Strooper B, Saftig P, Nukina N (2005) β Subunits of voltage-gated sodium channels are novel substrates of β-site amyloid precursor protein-cleaving enzyme (BACE1) and γ-secretase. J Biol Chem 280:23009–23017
Xu D-E, Zhang W-M, Yang ZZ, Zhu H-M, Yan K, Li S, Bagnard D, Dawe GS, Ma Q-H, Xiao Z-C (2014) Amyloid precursor protein at node of Ranvier modulates nodal formation. Cell Adh Migr 8:396–403
Xu J, Chen S, Ahmed SH, Chen H, Ku G, Goldberg MP, Hsu CY (2001) Amyloid-β peptides are cytotoxic to oligodendrocytes. J Neurosci 21:RC118-RC118
Xu M-Y, Xu Z-Q, Wang Y-J (2022) White Matter “Matters” in Alzheimer’s Disease. Neurosci Bull 38:323–326
Yang SY, Huh I-S, Cho EY, Choi MJ, Park T, Lee Y-S, Hong KS (2015) Association Study of ANK3 Polymorphism and Risk of Schizophrenia. Korean Journal of Biological Psychiatry 22:173–178
Yuan A, Yi Z, Wang Q, Sun J, Li Z, Du Y, Zhang C, Yu T, Fan J, Li H (2012) ANK3 as a risk gene for schizophrenia: new data in Han Chinese and meta analysis. Am J Med Genet B Neuropsychiatr Genet 159:997–1005
Yuan DJ, Yang G, Wu W, Li QF, Xu De, Ntim M, Jiang CY, Liu JC, Zhang Y, Wang YZ (2022) Reducing Nav1. 6 expression attenuates the pathogenesis of Alzheimer's disease by suppressing BACE1 transcription. Aging Cell:e13593
Zhai Y, Yamashita T, Nakano Y, Sun Z, Morihara R, Fukui Y, Ohta Y, Hishikawa N, Abe K (2016) Disruption of white matter integrity by chronic cerebral hypoperfusion in Alzheimer’s disease mouse model. J Alzheimers Dis 52:1311–1319
Zhang C, Susuki K, Zollinger DR, Dupree JL, Rasband MN (2013) Membrane domain organization of myelinated axons requires βII spectrin. J Cell Biol 203:437–443
Zhang J, Yang X, Zhou Y, Fox H, Xiong H (2019) Direct contacts of microglia on myelin sheath and Ranvier’s node in the corpus callosum in rats. J Biomed Res 33:192
Zhou T, Ahmad TK, Gozda K, Truong J, Kong J, Namaka M (2017) Implications of white matter damage in amyotrophic lateral sclerosis. Mol Med Rep 16:4379–4392
Funding
This work is supported by DST INSPIRE, Government of India.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing Interests
The authors declare no competing interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Dolma, S., Joshi, A. The Node of Ranvier as an Interface for Axo-Glial Interactions: Perturbation of Axo-Glial Interactions in Various Neurological Disorders. J Neuroimmune Pharmacol 18, 215–234 (2023). https://doi.org/10.1007/s11481-023-10072-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11481-023-10072-z