How axonal damage, a major prognostic factor of multiple sclerosis disability progression, is induced, is likely to be multifactorial. Whereas axonal injury has been identified as a consequence of myelin loss, the possibility of an additional direct damage is also suggested. In this context, recent data have highlighted the nodal and perinodal axonal domains of the myelinated neurons as potential targets of the disease process, opening new perspectives in multiple sclerosis pathophysiology.
NikicIMerklerDSorbaraCBrinkoetterMKreutzfeldtMBareyreFM. A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med2011; 17: 495–499.
2.
LassmannH. Axonal and neuronal pathology in multiple sclerosis: what have we learnt from animal models. Exp Neurol2010; 225: 2–8.
3.
BhatRSteinmanL. Innate and adaptive autoimmunity directed to the central nervous system. Neuron2009; 64: 123–132.
4.
ZhangYDaRRGuoWRenHMHilgenbergLGSobelRA. Axon reactive B cells clonally expanded in the cerebrospinal fluid of patients with multiple sclerosis. J Clin Immunol2005; 25: 254–164.
5.
BartosAFialovaLSoukupovaJKukalJMalbohanIPit’haJ. Elevated intrathecal antibodies against the medium neurofilament subunit in multiple sclerosis. J Neurol2007; 254: 20–25.
6.
KrishnamoorthyGSaxenaAMarsLTDominguesHSMenteleRBen-NunA. Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis. Nat Med2009; 15: 626–632.
7.
MatheyEKDerfussTStorchMKWilliamsKRHalesKWoolleyDR. Neurofascin as a novel target for autoantibody-mediated axonal injury. J Exp Med2007; 204: 2363–2372.
8.
DerfussTParikhKVelhinSBraunMMatheyEKrumbholzM. Contactin-2/TAG-1-directed autoimmunity is identified in multiple sclerosis patients and mediates gray matter pathology in animals. Proc Natl Acad Sci U S A2009; 106: 8302–8307.
9.
WaxmanSGRitchieJM. Molecular dissection of the myelinated axon. Ann Neurol1993; 33: 121–136.
10.
YuFHCatterallWA. Overview of the voltage-gated sodium channel family. Genome Biol2003; 4: 207.
11.
SalzerJL. Polarized domains of myelinated axons. Neuron2003; 40: 297–318.
12.
PoliakSPelesE. The local differentiation of myelinated axons at nodes of Ranvier. Nat Rev Neurosci2003; 4: 968–980.
13.
LeterrierCBrachetADargentBVacherH. Determinants of voltage-gated sodium channel clustering in neurons. Semin Cell Dev Biol2011; 22: 171–177.
14.
SusukiKRasbandMN. Molecular mechanisms of node of Ranvier formation. Curr Opin Cell Biol2008; 20: 616–623.
15.
GiraultJAPelesE. Development of nodes of Ranvier. Curr Opin Neurobiol2002; 12: 476–485.
16.
ShermanDLBrophyPJ. Mechanisms of axon ensheathment and myelin growth. Nat Rev Neurosci2005; 6: 683–690.
LabasqueMFaivre-SarrailhC. GPI-anchored proteins at the node of Ranvier. FEBS Lett2010; 584: 1787–1792.
19.
RasbandMN. Composition, assembly, and maintenance of excitable membrane domains in myelinated axons. Semin Cell Dev Biol2011; 22: 178–184.
20.
GriffithsIKlugmannMAndersonTYoolDThomsonCSchwabMH. Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science1998; 280: 1610–1613.
21.
DupreeJLCoetzeeTBlightASuzukiKPopkoB. Myelin galactolipids are essential for proper node of Ranvier formation in the CNS. J Neurosci1998; 18: 1642–1649.
22.
BoikoTRasbandMNLevinsonSRCaldwellJHMandelGTrimmerJS. Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon. Neuron2001; 30: 91–104.
23.
ArroyoEJXuTGrinspanJLambertSLevinsonSRBrophyPJ. Genetic dysmyelination alters the molecular architecture of the nodal region. J Neurosci2002; 22: 1726–1737.
24.
Lappe-SiefkeCGoebbelsSGravelMNickschELeeJBraunPE. Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nat Genet2003; 33: 366–374.
25.
CranerMJNewcombeJBlackJAHartleCCuznerMLWaxmanSG. 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 U S A2004; 101: 8168–8173.
26.
ComanIAigrotMSSeilheanDReynoldsRGiraultJAZalcB. Nodal, paranodal and juxtaparanodal axonal proteins during demyelination and remyelination in multiple sclerosis. Brain2006; 129: 3186–3195.
27.
HowellOPalserAPolitoAMelroseSZontaBScheiermannC. Disruption of neurofascin localization reveals early changes preceding demyelination and remyelination in multiple sclerosis. Brain2006; 129: 3173–3185.
28.
WolswijkGBalesarR. Changes in the expression and localization of the paranodal protein Caspr on axons in chronic multiple sclerosis. Brain2003; 126: 1638–1649.
29.
HowellOWRundleJLGargAKomadaMBrophyPJReynoldsR. Activated microglia mediate axoglial disruption that contributes to axonal injury in multiple sclerosis. J Neuropath Exp Neurol2010; 69: 1017–1033.
30.
CharlesPTaitSFaivre-SarrailhCBarbinGGunn-MooreFDenisenko-NehrbassN. Neurofascin is a glial receptor for the paranodin/Caspr–contactin axonal complex at the axoglial junction. Curr Biol2002; 12: 217–220.
31.
DerfussTLiningtonCHohlfeldRMeinlE. Axo-glial antigens as targets in multiple sclerosis: implications for axonal and grey matter injury. J Mol Med2010; 88: 753–761.