Myelin oligodendrocyte glycoprotein explained

Myelin oligodendrocyte glycoprotein (MOG) is a glycoprotein believed to be important in the myelination of nerves in the central nervous system (CNS). In humans this protein is encoded by the MOG gene.[1] [2] [3] It is speculated to serve as a necessary "adhesion molecule" to provide structural integrity to the myelin sheath and is known to develop late on the oligodendrocyte.

Molecular function

While the primary molecular function of MOG is not yet known, its likely role with the myelin sheath is either in sheath "completion and/or maintenance".[3] More specifically, MOG is speculated to be "necessary" as an "adhesion molecule" on the myelin sheath of the CNS to provide the structural integrity of the myelin sheath.[4] "

MOG's cDNA coding region in humans have been shown to be "highly homologous"[5] to rats, mice, and bovine, and hence highly conserved. This suggests "an important biological role for this protein".[3]

Physiology

The gene for MOG, found on chromosome 6 p21.3-p22,[6] was first sequenced in 1995. It is a transmembrane protein expressed on the surface of oligodendrocyte cell and on the outermost surface of myelin sheaths. "MOG is a quantitatively minor type I transmembrane protein,[7] and is found exclusively in the CNS. "A single Ig-domain is exposed to the extracellular space" and consequently allows autoantibodies easy access. and therefore is easily accessible to autoantibodies too. The MOG "primary nuclear transcript … is 15,561 nucleotides in length" and, for humans, it has eight exons which are "separated by seven introns". The introns "contain numerous DNA" sequences, among which are "14 Alu sequences within 3 introns", and have a range varying from 242 to 6484 bp.

Structure

Alternatively spliced human mRNA of the MOG gene form at least nine isoforms.[8]

The crystal structure of myelin oligodendrocyte glycoprotein was determined by x-ray diffraction at a resolution of 1.45 Angstroms, using protein from the Norway rat. This protein is 139 residues long, and is a member of the immunoglobulin superfamily.[9] The dssp secondary structure of the protein is 6% helical and 43% beta sheet: there are three short helical segments and ten beta strands.[10] The beta strands are within two antiparallel beta sheets that form an immunoglobulin-like beta-sandwich fold.[11] Several features of the protein structure suggest MOG has a role as an "adhesin in the completion and/or compaction of the myelin sheath." There is a "significant strip" of electronegative charge beginning near the N-terminus and running about half the length of the molecule. Also, MOG was shown to dimerize in solution, and the shape complementarity index is high at the dimer interface, suggesting a "biologically relevant MOG dimer."[12]

Synthesis

Developmentally, MOG is formed "very late on oligodendrocytes and the myelin sheath".

Role in disease

Non-inflammatory demyelinating diseases

Interest in MOG has centered on its role in demyelinating diseases. Some of them are not-inflammatory, such as adrenoleukodystrophy, vanishing white matter disease, and Rubella induced mental retardation.[13]

Anti-MOG associated inflammatory demyelinating diseases

See main article: antiMOG associated encephalomyelitis.

MOG has received much of its laboratory attention in studies dealing with MS. Several studies have shown a role for antibodies against MOG in the pathogenesis of MS,[14] though most of them were written before the discovery of NMO-IgG and the NMO spectrum of diseases.

Anti-MOG status is different depending whether it is measured by ELISA or by microarray (CBA). The proper way to identify it is by microarray, reacting patient serum with living cells, and detecting the binding IgG via a fluorescent-labeled secondary antibody.[15]

In animal models

Animal models of MS, namely Experimental Autoimmune Encephalomyelitis (EAE) models, have shown that "MOG-specific EAE models (of different animal strains) display/mirror human multiple sclerosis", but basically explains the part involved in the optic neuritis.[16] These models with anti-MOG antibodies have been investigated extensively and are considered the only antibodies with demyelinating capacity but again, EAE pathology is closer to NMO and ADEM than to the confluent demyelination observed in MS.

Anti-MOG antibodies have been shown to behave similarly to AQP4 antibodies in animal models,[16] and are considered a biomarker against the MS diagnosis[17] [18]

In seronegative neuromyelitis optica

Anti-MOG autoimmunity has been found to be involved in most AQP4-seronegative NMO[19] [20] and also in optic neuritis and some fulminant forms of ADEM.[21] MOG antibodies in NMOSD are variable depending on the seropositivity status.[22]

In other conditions

The presence of anti-MOG autoantibodies has been associated with the following conditions[23]

Notes and References

  1. Pham-Dinh D, Della Gaspera B, Kerlero de Rosbo N, Dautigny A . Structure of the human myelin/oligodendrocyte glycoprotein gene and multiple alternative spliced isoforms . Genomics . 29 . 2 . 345–52 . September 1995 . 8666381 . 10.1006/geno.1995.9995 .
  2. Pham-Dinh D, Jones EP, Pitiot G, Della Gaspera B, Daubas P, Mallet J, Le Paslier D, Fischer Lindahl K, Dautigny A . Physical mapping of the human and mouse MOG gene at the distal end of the MHC class Ib region . Immunogenetics . 42 . 5 . 386–91 . 1995 . 7590972 . 10.1007/bf00179400 . 8310478 .
  3. Roth MP, Malfroy L, Offer C, Sevin J, Enault G, Borot N, Pontarotti P, Coppin H . The human myelin oligodendrocyte glycoprotein (MOG) gene: complete nucleotide sequence and structural characterization . Genomics . 28 . 2 . 241–50 . July 1995 . 8530032 . 10.1006/geno.1995.1137 .
  4. Berger, T., Innsbruck Medical University Dept. of Neurology interviewed by S. Gillooly, Nov. 24, 2008.
  5. Pham-Dinh D, Allinquant B, Ruberg M, Della Gaspera B, Nussbaum JL, Dautigny A . Characterization and expression of the cDNA coding for the human myelin/oligodendrocyte glycoprotein . Journal of Neurochemistry . 63 . 6 . 2353–6 . December 1994 . 7964757 . 10.1046/j.1471-4159.1994.63062353.x . 2788720 .
  6. Pham-Dinh D, Mattei MG, Nussbaum JL, Roussel G, Pontarotti P, Roeckel N, Mather IH, Artzt K, Lindahl KF, Dautigny A . Myelin/oligodendrocyte glycoprotein is a member of a subset of the immunoglobulin superfamily encoded within the major histocompatibility complex . Proceedings of the National Academy of Sciences of the United States of America . 90 . 17 . 7990–4 . September 1993 . 8367453 . 47273 . 10.1073/pnas.90.17.7990 . 1993PNAS...90.7990P . free .
  7. Berger T, Reindl M . Multiple sclerosis: disease biomarkers as indicated by pathophysiology . Journal of the Neurological Sciences . 259 . 1–2 . 21–6 . August 2007 . 17367811 . 10.1016/j.jns.2006.05.070 . 23257594 .
  8. Boyle LH, Traherne JA, Plotnek G, Ward R, Trowsdale J . Splice variation in the cytoplasmic domains of myelin oligodendrocyte glycoprotein affects its cellular localisation and transport . Journal of Neurochemistry . 102 . 6 . 1853–62 . September 2007 . 17573820 . 2156149 . 10.1111/j.1471-4159.2007.04687.x .
  9. Breithaupt C, Schubart A, Zander H, Skerra A, Huber R, Linington C, Jacob U . Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein . Proceedings of the National Academy of Sciences of the United States of America . 100 . 16 . 9446–51 . August 2003 . 12874380 . 170938 . 10.1073/pnas.1133443100 . 2003PNAS..100.9446B . free .
  10. Kabsch W, Sander C . Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features . Biopolymers . 22 . 12 . 2577–637 . December 1983 . 6667333 . 10.1002/bip.360221211 . 29185760 .
  11. Murzin AG, Brenner SE, Hubbard T, Chothia C . SCOP: a structural classification of proteins database for the investigation of sequences and structures . Journal of Molecular Biology . 247 . 4 . 536–40 . April 1995 . 7723011 . 10.1016/S0022-2836(05)80134-2 .
  12. Clements CS, Reid HH, Beddoe T, Tynan FE, Perugini MA, Johns TG, Bernard CC, Rossjohn J . The crystal structure of myelin oligodendrocyte glycoprotein, a key autoantigen in multiple sclerosis . Proceedings of the National Academy of Sciences of the United States of America . 100 . 19 . 11059–64 . September 2003 . 12960396 . 196926 . 10.1073/pnas.1833158100 . 2003PNAS..10011059C . free .
  13. Cong H, Jiang Y, Tien P . Identification of the myelin oligodendrocyte glycoprotein as a cellular receptor for rubella virus . Journal of Virology . 85 . 21 . 11038–47 . November 2011 . 21880773 . 3194935 . 10.1128/JVI.05398-11 .
  14. Berger T, Rubner P, Schautzer F, Egg R, Ulmer H, Mayringer I, Dilitz E, Deisenhammer F, Reindl M . Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event . The New England Journal of Medicine . 349 . 2 . 139–45 . July 2003 . 12853586 . 10.1056/NEJMoa022328 . free .
  15. Ichiro Nakashima, Anti-myelin oligodendrocyte glycoprotein antibody in demyelinating diseases http://onlinelibrary.wiley.com/doi/10.1111/cen3.12262/full
  16. Kezuka T, Usui Y, Yamakawa N, Matsunaga Y, Matsuda R, Masuda M, Utsumi H, Tanaka K, Goto H . Relationship between NMO-antibody and anti-MOG antibody in optic neuritis . Journal of Neuro-Ophthalmology . 32 . 2 . 107–10 . June 2012 . 22157536 . 10.1097/WNO.0b013e31823c9b6c . 46667141 . free .
  17. Ketelslegers IA, Van Pelt DE, Bryde S, Neuteboom RF, Catsman-Berrevoets CE, Hamann D, Hintzen RQ . Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort . Multiple Sclerosis . 21 . 12 . 1513–20 . October 2015 . 25662345 . 10.1177/1352458514566666 . 25321614 .
  18. Kitley J, Woodhall M, Waters P, Leite MI, Devenney E, Craig J, Palace J, Vincent A . Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype . Neurology . 79 . 12 . 1273–7 . September 2012 . 22914827 . 10.1212/WNL.0b013e31826aac4e . 855313 .
  19. Pröbstel AK, Rudolf G, Dornmair K, Collongues N, Chanson JB, Sanderson NS, Lindberg RL, Kappos L, de Seze J, Derfuss T . Anti-MOG antibodies are present in a subgroup of patients with a neuromyelitis optica phenotype . Journal of Neuroinflammation . 12 . 1 . 46 . 2015 . 25889963 . 10.1186/s12974-015-0256-1 . 4359547 . free .
  20. CYNTHIA MCKELVEY, Press Report, What's the Role of Myelin Oligodendrocyte Glycoprotein in NMO? http://www.msdiscovery.org/news/news_synthesis/14008-what%E2%80%99s-role-myelin-oligodendrocyte-glycoprotein-nmo
  21. Di Pauli F, Höftberger R, Reindl M, Beer R, Rhomberg P, Schanda K, Sato D, Fujihara K, Lassmann H, Schmutzhard E, Berger T . Fulminant demyelinating encephalomyelitis: Insights from antibody studies and neuropathology . Neurology: Neuroimmunology & Neuroinflammation . 2 . 6 . e175 . December 2015 . 26587556 . 10.1212/NXI.0000000000000175 . 4635550.
  22. Berger T, Reindl M . Antibody biomarkers in CNS demyelinating diseases - a long and winding road . European Journal of Neurology . 22 . 8 . 1162–8 . August 2015 . 26010364 . 10.1111/ene.12759 . 39301229 .
  23. Reindl M, Di Pauli F, Rostásy K, Berger T . The spectrum of MOG autoantibody-associated demyelinating diseases . Nature Reviews. Neurology . 9 . 8 . 455–61 . August 2013 . 23797245 . 10.1038/nrneurol.2013.118 . 7219279 .
  24. Spadaro M, Gerdes LA, Mayer MC, Ertl-Wagner B, Laurent S, Krumbholz M, Breithaupt C, Högen T, Straube A, Giese A, Hohlfeld R, Lassmann H, Meinl E, Kümpfel T . Histopathology and clinical course of MOG-antibody-associated encephalomyelitis . Annals of Clinical and Translational Neurology . 2 . 3 . 295–301 . March 2015 . 25815356 . 10.1002/acn3.164 . 4369279.
  25. Baumann M, Hennes EM, Schanda K, Karenfort M, Kornek B, Seidl R, Diepold K, Lauffer H, Marquardt I, Strautmanis J, Syrbe S, Vieker S, Höftberger R, Reindl M, Rostásy K . Children with multiphasic disseminated encephalomyelitis and antibodies to the myelin oligodendrocyte glycoprotein (MOG): Extending the spectrum of MOG antibody positive diseases . Multiple Sclerosis (Houndmills, Basingstoke, England) . 22. 14. 1821–1829. 2016 . 26869530 . 10.1177/1352458516631038 . 30428892 .

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