Skip to main content
NCBI home page
Neuroscience Bulletin logoLink to Neuroscience Bulletin
. 2013 Apr 5;29(2):144–154. doi: 10.1007/s12264-013-1317-z

Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges

Yueting Zhang 11317, Taylor B Guo 11317, Hongtao Lu 11317,✉
PMCID: PMC5561877  PMID: 23558587

Abstract

Multiple sclerosis (MS) is a chronic and devastating autoimmune demyelinating disease of the central nervous system. With the increased understanding of the pathophysiology of this disease in the past two decades, many disease-modifying therapies that primarily target adaptive immunity have been shown to prevent exacerbations and new lesions in patients with relapsing-remitting MS. However, these therapies only have limited efficacy on the progression of disability. Increasing evidence has pointed to innate immunity, axonal damage and neuronal loss as important contributors to disease progression. Remyelination of denuded axons is considered an effective way to protect neurons from damage and to restore neuronal function. The identification of several key molecules and pathways controlling the differentiation of oligodendrocyte progenitor cells and myelination has yielded clues for the development of drug candidates that directly target remyelination and neuroprotection. The long-term efficacy of this strategy remains to be evaluated in clinical trials. Here, we provide an overview of current and emerging therapeutic concepts, with a focus on the opportunities and challenges for the remyelination approach to the treatment of MS.

Keywords: multiple sclerosis, myelination, neurodegeneration, oligodendrocytes, disease progression, disease modifying therapy, drug target, animal models

References

  • [1].Kuhlmann T, Miron V, Cui Q, Wegner C, Antel J, Brück W. Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. Brain. 2008;131:1749–1758. doi: 10.1093/brain/awn096. [DOI] [PubMed] [Google Scholar]
  • [2].Wolswijk G. Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J Neurosci. 1998;18:601–609. doi: 10.1523/JNEUROSCI.18-02-00601.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [3].Chang A, Tourtellotte W, Rudick R, Trapp B. Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med. 2002;346:165–173. doi: 10.1056/NEJMoa010994. [DOI] [PubMed] [Google Scholar]
  • [4].Weiner H. A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis. J Neurol. 2008;255:3–11. doi: 10.1007/s00415-008-1002-8. [DOI] [PubMed] [Google Scholar]
  • [5].Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Annals Neurol. 2000;47:707–717. doi: 10.1002/1531-8249(200006)47:6<707::AID-ANA3>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
  • [6].Xiao L, Guo D, Hu C, Shen W, Shan L, Li C, et al. Diosgenin promotes oligodendrocyte progenitor cell differentiation through estrogen receptor-mediated ERK1/2 activation to accelerate remyelination. Glia. 2012;60:1037–1052. doi: 10.1002/glia.22333. [DOI] [PubMed] [Google Scholar]
  • [7].Silvestroff L, Bartucci S, Pasquini J, Franco P. Cuprizoneinduced demyelination in the rat cerebral cortex and thyroid hormone effects on cortical remyelination. Exp Neurol. 2012;235:357–367. doi: 10.1016/j.expneurol.2012.02.018. [DOI] [PubMed] [Google Scholar]
  • [8].Franco P, Silvestroff L, Soto E, Pasquini J. Thyroid hormones promote differentiation of oligodendrocyte progenitor cells and improve remyelination after cuprizone-induced demyelination. Exp Neurol. 2008;212:458–467. doi: 10.1016/j.expneurol.2008.04.039. [DOI] [PubMed] [Google Scholar]
  • [9].Raff M, Lillien L, Richardson W, Burne J, Noble M. Platelet derived growth factor from astrocytes drives the clock that times oligodendrocyte development in culture. Nature. 1988;333:562–565. doi: 10.1038/333562a0. [DOI] [PubMed] [Google Scholar]
  • [10].Watkins T, Emery B, Mulinyawe S, Barres B. Distinct stages of myelination regulated by gamma-secretase and astrocytes in a rapidly myelinating CNS coculture system. Neuron. 2008;60:555–569. doi: 10.1016/j.neuron.2008.09.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [11].Jeffery N, Blakemore W. Remyelination of mouse spinal cord axons demyelinated by local injection of lysolecithin. J Neurocytol. 1995;24:775–781. doi: 10.1007/BF01191213. [DOI] [PubMed] [Google Scholar]
  • [12].Matsushima G, Morell P. The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol. 2001;11:107–116. doi: 10.1111/j.1750-3639.2001.tb00385.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [13].Kirby BB, Takada N, Latimer AJ, Shin J, Carney TJ, Kelsh RN, et al. In vivo. Nat Neurosci. 2006;9:1506–1511. doi: 10.1038/nn1803. [DOI] [PubMed] [Google Scholar]
  • [14].Lyons DA, Naylor SG, Scholze A, Talbot WS. Kif1b is essential for mRNA localization in oligodendrocytes and development of myelinated axons. Nat Genet. 2009;41:854–858. doi: 10.1038/ng.376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [15].Harsan L, Steibel J, Zaremba A, Agin A, Sapin R, Poulet P, et al. Recovery from chronic demyelination by thyroid hormone therapy: myelinogenesis induction and assessment by diffusion tensor magnetic resonance imaging. J Neurosci. 2008;28:14189–14201. doi: 10.1523/JNEUROSCI.4453-08.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [16].Kondo T, Raff M. Basic helix-loop-helix proteins and the timing of oligodendrocyte differentiation. Development. 2000;127:2989–2998. doi: 10.1242/dev.127.14.2989. [DOI] [PubMed] [Google Scholar]
  • [17].Lu Q, Sun T, Zhu Z, Ma N, Garcia M, Stiles C, et al. Common developmental requirement for olig function indicates a motor neuron/oligodendrocyte connection. Cell. 2002;109:75–86. doi: 10.1016/S0092-8674(02)00678-5. [DOI] [PubMed] [Google Scholar]
  • [18].Lu QR, Park JK, Noll E, Chan JA, Alberta J, Yuk D, et al. oligodendrocyte lineage genes (OLIG) as molecular markers for human glial brain tumors. Proc Natl Acad Sci U S A. 2001;98:10851–10856. doi: 10.1073/pnas.181340798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [19].Qi Y, Cai J, Wu Y, Wu R, Lee J, Fu H, et al. Control of oligodendrocyte differentiation by the Nkx2.2 homeodomain transcription factor. Development. 2001;128:2723–2733. doi: 10.1242/dev.128.14.2723. [DOI] [PubMed] [Google Scholar]
  • [20].Zhou Q, Wang S, Anderson DJ. Identification of a novel family of oligodendrocyte lineage-specific basic helix-loop-helix transcription factors. Neuron. 2000;25:331–343. doi: 10.1016/S0896-6273(00)80898-3. [DOI] [PubMed] [Google Scholar]
  • [21].He Y, Dupree J, Wang J, Sandoval J, Li J, Liu H, et al. The transcription factor Yin Yang 1 is essential for oligodendrocyte progenitor differentiation. Neuron. 2007;55:217–230. doi: 10.1016/j.neuron.2007.06.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].Finzsch M, Stolt CC, Lommes P, Wegner M. Sox9 and Sox10 influence survival and migration of oligodendrocyte precursors in the spinal cord by regulating PDGF receptor alpha expression. Development. 2008;135:637–646. doi: 10.1242/dev.010454. [DOI] [PubMed] [Google Scholar]
  • [23].Wang S, Dulin J, Wu H, Hurlock E, Lee S, Jansson K, et al. An oligodendrocyte-specific zinc-finger transcription regulator cooperates with olig2 to promote oligodendrocyte differentiation. Development. 2006;133:3389–3398. doi: 10.1242/dev.02522. [DOI] [PubMed] [Google Scholar]
  • [24].Emery B, Agalliu D, Cahoy JD, Watkins TA, Dugas JC, Mulinyawe SB, et al. Myelin gene regulatory factor is a critical transcriptional regulator required for CNS myelination. Cell. 2009;138:172–185. doi: 10.1016/j.cell.2009.04.031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [25].Shen YH, Avila RL, Emery B, Traka M, Lin W, Watkins T, et al. Zfp191 is required by oligodendrocytes for CNS myelination. Genes Dev. 2010;24:301–311. doi: 10.1101/gad.1864510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Chen Y, Wu H, Wang S, Koito H, Li J, Ye F, et al. The oligodendrocyte-specific G protein-coupled receptor Gpr17 is a cell-intrinsic timer of myelination. Nat Neurosci. 2009;12:1398–1406. doi: 10.1038/nn.2410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [27].Koenning M, Jackson S, Hay CM, Faux C, Kilpatrick TJ, Willingham M, et al. Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS. J Neurosci. 2012;32:12528–12542. doi: 10.1523/JNEUROSCI.1069-12.2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [28].Huang J, Jarjour A, Oumesmar B, Kerninon C, Williams A, Krezel W, et al. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat Neurosci. 2011;14:45–55. doi: 10.1038/nn.2702. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [29].Xin M, Yue T, Ma Z, Wu FF, Gow A, Lu QR. Myelinogenesis and axonal recognition by oligodendrocytes in brain are uncoupled in olig1-null mice. J Neurosci. 2005;25:1354–1365. doi: 10.1523/JNEUROSCI.3034-04.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [30].Lecca D, Trincavelli ML, Gelosa P, Sironi L, Ciana P, Fumagalli M, et al. The recently identified P2Y-like receptor GPR17 is a sensor of brain damage and a new target for brain repair. PLoS One. 2008;3:1–15. doi: 10.1371/journal.pone.0003579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [31].Fumagalli M, Daniele S, Lecca D, Lee P, Parravicini C, Fields R, et al. Phenotypic changes, signaling pathway, and functional correlates of GPR17-expressing neural precursor cells during oligodendrocyte differentiation. J Biol Chem. 2011;286:10593–10604. doi: 10.1074/jbc.M110.162867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [32].Ceruti S, Viganò F, Boda E, Ferrario S, Magni G, Boccazzi M, et al. Expression of the new P2Y-like receptor GPR17 during oligodendrocyte precursor cell maturation regulates sensitivity to ATP-induced death. Glia. 2011;59:363–378. doi: 10.1002/glia.21107. [DOI] [PubMed] [Google Scholar]
  • [33].Wang S, Sdrulla AD, diSibio G, Bush G, Nofziger D, Hicks C, et al. Notch receptor activation inhibits oligodendrocyte differentiation. Neuron. 1998;21:63–75. doi: 10.1016/S0896-6273(00)80515-2. [DOI] [PubMed] [Google Scholar]
  • [34].Hu QD, Ang BT, Karsak M, Hu WP, Cui XY, Duka T, et al. F3/ contactin acts as a functional ligand for Notch during oligodendrocyte maturation. Cell. 2003;115:163–175. doi: 10.1016/S0092-8674(03)00810-9. [DOI] [PubMed] [Google Scholar]
  • [35].John G, Shanker S, Shafit-Zagardo B, Massimi A, Lee SC, Raine CS, et al. Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nat Med. 2002;8:1115–1121. doi: 10.1038/nm781. [DOI] [PubMed] [Google Scholar]
  • [36].Zhang Y, Argaw AT, Gurfein BT, Zameer A, Snyder BJ, Ge C, et al. Notch1 signaling plays a role in regulating precursor differentiation during CNS remyelination. Proc Natl Acad Sci U S A. 2009;106:19162–19167. doi: 10.1073/pnas.0902834106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [37].Stidworthy MF, Genoud S, Li WW, Leone DP, Mantei N, Suter U, et al. Notch1 and Jagged1 are expressed after CNS demyelination, but are not a major rate-determining factor during remyelination. Brain. 2004;127:1928–1941. doi: 10.1093/brain/awh217. [DOI] [PubMed] [Google Scholar]
  • [38].Fancy SP, Baranzini SE, Zhao C, Yuk DI, Irvine KA, Kaing S, et al. Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS. Genes Dev. 2009;23:1571–1585. doi: 10.1101/gad.1806309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [39].Ye F, Chen Y, Hoang T, Montgomery R, Zhao X, Bu H, et al. HDAC1 and HDAC2 regulate oligodendrocyte differentiation by disrupting β-Catenin-TCF interaction. Nat Neurosci. 2009;12:829–838. doi: 10.1038/nn.2333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [40].Fancy S, Harrington E, Yuen T, Silbereis J, Zhao C, Baranzini S, et al. Axin2 as regulatory and therapeutic target in new born brain injury and remyelination. Nat Neurosci. 2011;14:1009–1016. doi: 10.1038/nn.2855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [41].Gross R, Mehler M, Mabie P, Zang Z, Santschi L, Kessler J. Bone morphogenetic proteins promote astroglial lineage commitment by mammalian subventricular zone progenitor cells. Neuron. 1996;17:595–606. doi: 10.1016/S0896-6273(00)80193-2. [DOI] [PubMed] [Google Scholar]
  • [42].Samanta J, Kessler J. Interactions between ID and OLIG proteins mediate the inhibitory effects of BMP4 on oligodendroglial differentiation. Development. 2004;131:4131–4142. doi: 10.1242/dev.01273. [DOI] [PubMed] [Google Scholar]
  • [43].Sabo J, Aumann T, Merlo D, Kilpatrick T, Cate H. Remyelination is altered by bone morphogenic protein signaling in demyelinated lesions. J Neurosci. 2011;31:4504–4510. doi: 10.1523/JNEUROSCI.5859-10.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [44].Cate H, Sabo J, Merlo D, Kemper D, Aumann T, Robinson J, et al. Modulation of bone morphogenic protein signalling alters numbers of astrocytes and oligodendroglia in the subventricular zone during cuprizone-induced demyelination. J Neurochem. 2010;115:11–22. doi: 10.1111/j.1471-4159.2010.06660.x. [DOI] [PubMed] [Google Scholar]
  • [45].Wu M, Hernandez M, Shen S, Sabo JK, Kelkar D, Wang J, et al. Differential modulation of the oligodendrocyte transcriptome by sonic hedgehog and bone morphogenetic protein 4 via opposing effects on histone acetylation. J Neurosci. 2012;32:6651–6664. doi: 10.1523/JNEUROSCI.4876-11.2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [46].Cheng X, Wang Y, He Q, Qiu M, Whittemore SR, Cao Q. Bone morphogenetic protein signaling and olig1/2 interact to regulate the differentiation and maturation of adult oligodendrocyte precursor cells. Stem Cells. 2007;25:3204–3214. doi: 10.1634/stemcells.2007-0284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [47].Mi S, Lee X, Shao Z, Thill G, Ji B, Relton J, et al. LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nat Neurosci. 2004;7:221–228. doi: 10.1038/nn1188. [DOI] [PubMed] [Google Scholar]
  • [48].Mi S, Miller RH, Lee X, Scott ML, Shulag-Morskaya S, Shao Z, et al. LINGO-1 negatively regulates myelination by oligodendrocytes. Nat Neurosci. 2005;8:745–751. doi: 10.1038/nn1460. [DOI] [PubMed] [Google Scholar]
  • [49].Mi S, Hu B, Hahm K, Luo Y, Kam Hui ES, Yuan Q, et al. LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis. Nat Med. 2007;10:1228–1233. doi: 10.1038/nm1664. [DOI] [PubMed] [Google Scholar]
  • [50].Lee X, Yang Z, Shao Z, Rosenberg SS, Levesque M, Pepinsky RB, et al. NGF regulates the expression of axonal LINGO-1 to inhibit oligodendrocyte differentiation and myelination. J Neurosci. 2007;27:220–225. doi: 10.1523/JNEUROSCI.4175-06.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [51].Zhao XH, Jin WL, Ju G. An in vitro study on the involvement of LINGO-1 and Rho GTPases in Nogo-A regulated differentiation of oligodendrocyte precursor cells. Mol Cell Neurosci. 2007;36:260–269. doi: 10.1016/j.mcn.2007.07.008. [DOI] [PubMed] [Google Scholar]
  • [52].Mi S, Miller R, Tang W, Lee X, Hu B, Wu W, et al. Promotion of central nervous system remyelination by induced differentiation of oligodendrocyte precursor cells. Annals Neurol. 2009;65:304–315. doi: 10.1002/ana.21581. [DOI] [PubMed] [Google Scholar]
  • [53].Satoh J, Tabunoki H, Yamamura T, Arima K, Konno H. TROY and LINGO-1 expression in astrocytes and macrophages/ microglia in multiple sclerosis lesions. Neuropathol Appl Neurobiol. 2007;33:99–107. doi: 10.1111/j.1365-2990.2006.00787.x. [DOI] [PubMed] [Google Scholar]
  • [54].Maness P, Schachner M. Neural recognition molecules of the immunoglobulin superfamily: signaling transducers of axon guidance and neuronal migration. Nat Neurosci. 2007;10:19–27. doi: 10.1038/nn1827. [DOI] [PubMed] [Google Scholar]
  • [55].Trotter J, Bitter-Suermann D, Schachner M. Differentiation-regulated loss of the polysialylated embryonic form and expression of the different polypeptides of the neural cell adhesion molecule by cultured oligodendrocytes and myelin. J Neurosci Res. 1989;22:369–383. doi: 10.1002/jnr.490220402. [DOI] [PubMed] [Google Scholar]
  • [56].Seki T, Arai Y. Expression of highly polysialylated NCAM in the neocortex and piriform cortex of the developing and the adult rat. Anat Embryol (Berl) 1991;184:395–401. doi: 10.1007/BF00957900. [DOI] [PubMed] [Google Scholar]
  • [57].Seki T, Arai Y. Distribution and possible roles of the highly polysialylated neural cell adhesion molecule (NCAM-H) in the developing and adult central nervous system. Neurosci Res. 1993;17:265–290. doi: 10.1016/0168-0102(93)90111-3. [DOI] [PubMed] [Google Scholar]
  • [58].Oumesmar BN, Vignais L, Duhamel-Clerin E, Avellana-Adalid V, Rougon G, Baron-Van Evercooren A. Expression of the highly polysialylated neural cell adhesion molecule during postnatal myelination and following chemically induced demyelination of the adult mouse spinal cord. Eur J Neurosci. 1995;7:480–491. doi: 10.1111/j.1460-9568.1995.tb00344.x. [DOI] [PubMed] [Google Scholar]
  • [59].Charles P, Hernandez MP, Stankoff B, Aigrot MS, Colin C, Rougon G, et al. Negative regulation of central nervous system myelination by polysialylated-neural cell adhesion molecule. Proc Natl Acad Sci U S A. 2000;97:7585–7590. doi: 10.1073/pnas.100076197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [60].Fewou SN, Ramakrishnan H, Bussow H, Gieselmann V, Eckhardt M. Down-regulation of polysialic acid is required for efficient myelin formation. J Biol Chem. 2007;282:16700–16711. doi: 10.1074/jbc.M610797200. [DOI] [PubMed] [Google Scholar]
  • [61].Charles P, Reynolds R, Seilhean D, Rougon G, Aigrot MS, Niezgoda A, et al. Re-expression of PSA-NCAM by demyelinated axons: an inhibitor of remyelination in multiple sclerosis? Brain. 2002;125:1972–1979. doi: 10.1093/brain/awf216. [DOI] [PubMed] [Google Scholar]
  • [62].Laursen L, Chan C, Ffrench-Constant C. An integrin-contactin complex regulates CNS myelination by differential Fyn phosphorylation. J Neurosci. 2009;29:9174–9185. doi: 10.1523/JNEUROSCI.5942-08.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [63].White R, Gonsior C, Krämer-Albers E, Stöhr N, Hüttelmaier S, Trotter J. Activation of oligodendroglial Fyn kinase enhances translation of mRNAs transported in hnRNP A2-dependent RNA granules. J Cell Biol. 2009;181:579–586. doi: 10.1083/jcb.200706164. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [64].Kubasak MD, Hedlund E, Roy RR, Carpenter EM, Edgerton VR, Phelps PE. L1 CAM expression is increased surrounding the lesion site in rats with complete spinal cord transection as neonates. Exp Neurol. 2005;194(2):363–375. doi: 10.1016/j.expneurol.2005.02.013. [DOI] [PubMed] [Google Scholar]
  • [65].Martini R, Schachner M. immunoelectron microscopic localization of neural cell adhesion molecules (L1, N-CAM, and myelin-associated glycoprotein) in regenerating adult mouse sciatic nerve. J Cell Biol. 1988;106:1735–1746. doi: 10.1083/jcb.106.5.1735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [66].Roonprapunt C, Huang W, Grill R, Friedlander D, Grumet M, Chen S, et al. Soluble cell adhesion molecule L1-Fc promotes locomotor recovery in rats after spinal cord injury. J Neurotrauma. 2003;20:871–882. doi: 10.1089/089771503322385809. [DOI] [PubMed] [Google Scholar]
  • [67].Xu G, Nie DY, Wang WZ, Zhang PH, Shen J, Ang BT, et al. optic nerve regeneration in polyglycolic acid-chitosan conduits coated with recombinant L1-Fc. Neuroreport. 2004;15:2167–2172. doi: 10.1097/00001756-200410050-00004. [DOI] [PubMed] [Google Scholar]
  • [68].Zhang Y, Bo X, Schoepfer R, Holtmaat AJ, Verhaagen J, Emson PC, et al. Growth-associated protein GAP-43 and L1 act synergistically to promote regenerative growth of Purkinje cell axons in vivo. Proc Natl Acad Sci U S A. 2005;102:14883–14888. doi: 10.1073/pnas.0505164102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [69].Schmidt F, Eijnden M, Gobert R, Saborio G, Carboni S, Alliod C, et al. Identification of VHY/Dusp15 as a regulator of oligodendrocyte differentiation through a systematic genomics approach. PLoS One. 2012;7:e40457. doi: 10.1371/journal.pone.0040457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [70].Bernard F, Moreau-Fauvarque C, Heitz-Marchaland C, Zagar Y, Dumas L, Fouquet S, et al. Role of transmembrane semaphorin Sema6A in oligodendrocyte differentiation and myelination. Glia. 2012;60:1590–604. doi: 10.1002/glia.22378. [DOI] [PubMed] [Google Scholar]
  • [71].Fancy S, Glasgow S, Finley M, Rowitch D, Deneen B. Evidence that nuclear factor IA inhibits repair after white matter injury. Annals Neurol. 2012;72:224–233. doi: 10.1002/ana.23590. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [72].Kuboyama K, Fujikawa A, Masumura M, Suzuki R, Matsumoto M, Noda M. Protein tyrosine phosphatase receptor type z negatively regulates oligodendrocyte differentiation and myelination. PLoS One. 2012;7:e48797. doi: 10.1371/journal.pone.0048797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [73].Bö L, Vedeler CA, Nyland HI, Trapp BD, Mök SJ. Subpial demyelination in the cerebral cortex of multiple sclerosis patients. J Neuropathol Exp Neurol. 2003;62:723–732. doi: 10.1093/jnen/62.7.723. [DOI] [PubMed] [Google Scholar]
  • [74].Peterson JW, Bö L, Mök S, Chang A, Trapp BD. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol. 2001;50:389–400. doi: 10.1002/ana.1123. [DOI] [PubMed] [Google Scholar]
  • [75].Kutzelnigg A, Lucchinetti CF, Stadekmann C, Brück W, Rauschka H, Bergmann M, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain. 2005;128:2705–2712. doi: 10.1093/brain/awh641. [DOI] [PubMed] [Google Scholar]
  • [76].Lucchinetti CF, Popescu BF, Bunyan RF, Moll NM, Roemer SF, Lassmann H, et al. Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med. 2011;365:2188–2197. doi: 10.1056/NEJMoa1100648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [77].Howell O, Reeves C, Nicholas R, Carassiti D, Radotra B, Gentleman S, et al. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain. 2011;134:2755–2771. doi: 10.1093/brain/awr182. [DOI] [PubMed] [Google Scholar]
  • [78].Victora GD, Nussenzweig MC. Germinal centers. Annu Rev immunol. 2012;30:429–457. doi: 10.1146/annurev-immunol-020711-075032. [DOI] [PubMed] [Google Scholar]
  • [79].Han M, Huwang S, Roy D, Lundgren D, Price J, Ousman S, et al. Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature. 2008;451:1076–1081. doi: 10.1038/nature06559. [DOI] [PubMed] [Google Scholar]
  • [80].MacKay A, Whittall K, Adler J, Li D, Paty D, Graeb D. In vivo visualization of myelin water in brain by magnetic resonance. Magn Reson Med. 1994;31:673–677. doi: 10.1002/mrm.1910310614. [DOI] [PubMed] [Google Scholar]
  • [81].Narayanan S, Francis SJ, Sled JG, Santos AC, Antel S, Levesque I, et al. Axonal injury in the cerebral normalappearing white matter of patients with multiple sclerosis is related to concurrent demyelination in lesions but not to concurrent demyelination in normal-appearing white matter. Neuroimage. 2006;29:637–642. doi: 10.1016/j.neuroimage.2005.07.017. [DOI] [PubMed] [Google Scholar]
  • [82].Stankoff B, Freeman L, Aigrot MS, Chardain A, Dolle F, Williams A, et al. imaging central nervous system myelin by positron emission tomography in multiple sclerosis using [methyl-(1)(1)C]-2-(4′-methylaminophenyl)-6-hydroxybenzothiazole. Ann Neurol. 2011;69:673–680. doi: 10.1002/ana.22320. [DOI] [PubMed] [Google Scholar]
  • [83].Stankoff B, Wang Y, Bottlaender M, Aigrot MS, Dolle F, Wu C, et al. Imaging of CNS myelin by positron-emission tomography. Proc Natl Acad Sci U S A. 2006;103:9304–9309. doi: 10.1073/pnas.0600769103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [84].Joubert L, Foucault I, Sagot Y, Bernasconi L, Duval F, Alliod C, et al. Chemical inducers and transcriptional markers of oligodendrocyte differentiation. J Neurosci Res. 2010;88:2546–2557. doi: 10.1002/jnr.22434. [DOI] [PubMed] [Google Scholar]
  • [85].Taupin P. Thirteen compounds promoting oligodendrocyte progenitor cell differentiation and remyelination for treating multiple sclerosis: WO2010054307. Expert Opin Ther Pat. 2010;20:1767–1773. doi: 10.1517/13543776.2010.528393. [DOI] [PubMed] [Google Scholar]

Articles from Neuroscience Bulletin are provided here courtesy of Springer

RESOURCES