Myelin oligodendrocyte glycoprotein

myelin oligodendrocyte glycoprotein
Crystal structure of rat myelin oligodendrocyte glycoprotein.[1]
Available structures PDB 1py9
Identifiers
Symbols	MOG; MGC26137
External IDs	OMIM: 159465 MGI: 97435 HomoloGene: 110875 GeneCards: MOG Gene
Gene Ontology Molecular function • protein binding • sodium:dicarboxylate symporter activity Cellular component • membrane • integral to membrane • plasma membrane Biological process • cell adhesion • dicarboxylic acid transport • central nervous system development Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	4340	17441
Ensembl	ENSG00000204655	ENSMUSG00000076439
UniProt	Q16653	Q61885
RefSeq (mRNA)	NM_002433	NM_010814
RefSeq (protein)	NP_001008229	NP_034944
Location (UCSC)	Chr 6: 29.73 – 29.75 Mb	Chr 17: 37.15 – 37.16 Mb
PubMed search	[1]	[2]

Myelin Oligodendrocyte Glycoprotein (MOG) is a glycoprotein believed to be important in the process of myelinization of nerves in the central nervous system (CNS). In humans this protein is encoded by the MOG gene.^[2][3][4] 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.^[5]

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”.^[4] 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.^[5]”

MOG’s cDNA coding region in humans have been shown to be “highly homologous”^[6] to rats, mice, and bovine, and hence highly conserved. This suggests “an important biological role for this protein”.^[4]

Physiology

The gene for MOG, found on chromosome 6p21.3-p22,^[7] was first sequenced in 1995.^[3] 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,^[8] and is found exclusively in the CNS. “A single Ig-domain is exposed to the extracellular space"^[8] and consequently allows autoantibodies easy access. and therefore easily accessible for autoantibodies.^[4][8] The MOG “primary nuclear transcript … is 15,561 nucleotides in length"^[4] and, for humans, it has eight exons which are “separated by seven introns".^[4] The introns "contain numerous reptitive DNA^[4]" sequences, among which is "14 Alu sequences within 3 introns",^[4] and have a range varying from 242 to 6484 bp.

Structure

Because of alternatively spliced from human mRNA of MOG gene forming at least nine isoforms.^[9]

The crystal structure of myelin oligodendrocyte glycoprotein was determined by x-ray diffraction at a resolution of 1.45 Angstrom, using protein from the Norway rat. This protein is 139 residues long, and is a member of the immunoglobulin superfamily.^[1] 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".^[5]

Role in disease

Interest in MOG has centered on its role in demyelinating diseases, such as adrenoleukodystrophy, vanishing white matter disease, multiple sclerosis (MS) and Rubella induced mental retardation.^[13] It is a target antigen that leads to autoimmune-mediated demyelation. 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.^[5][14] Animal models of MS, EAE, have shown that “MOG-specific EAE models (of different animal strains) display/mirror human multiple sclerosis",^[5] as is demonstrated by the demyelinating capacity and by the topography of the lesions. These models have shown that the anti-MOG antibodies are the cause of the demyelination. These models with anti-MOG antibodies have been investigated extensively and “are the only antibodies with demyelinating capacity”.^[5]

Multiple Sclerosis

The pathogenic process to MS is currently unknown, but there are a couple of theories based on current research. One of the current leading theories is "antibody-mediated demyelination", where the immune system is attacking the body: specifically the central nervous system, leading to demyelination. In this theory, target antigens mark the body for antibodies to attack. Going into more detail, it is the T-cell and B-cells that “have been widely implicated in the MS pathogenesis through an antibody-mediated demylination”.^[15] Two suspected antigens involved in pathogenesis of MS are commonly investigated among a large number of various antigens in some of the studies that will be mentioned. One is myelin basic protein (MBP), which has already been shown to have many antibodies present against it in early MS.^[14] The other is myelin oligodendrocyte glycoproteins (MOG). Both "have been identified as targets of the immune response".^[15] Tying back into the “antibody-mediated demyelination” theory, these antibodies that result from the immune response might be factors that contribute to the development of multiple sclerosis.^[15]

In one particular study,^[14] the experiment calls for serums of anti-MOG and anti-MBP to test their tendencies on causing conversion of a "clinically isolated syndrome" in a patient to develop into "clinically definite" MS. There is the control group, who receives no serum, the group who receives both serums, and a group who receives only the anti-MOG serum. The results revealed that 23 percent of the patients who received no serum had a relapse after 45.1±13.7 months. 83 percent of the patients who had only the anti-MOG serum had a relapsed after 14.6±9.6 months. All but one of the 22 patients who had both serums relapsed, and happened in 7.5 ± 4.4 months.^[14]

Given the results, a patient with a “clinically isolated syndrome” that appears headed for MS still has a highly varied prognosis and does not necessarily become “clinically definite” MS. The results are consistent with previous data on the disease. For instance, 30-40 percent of MS cases are said to be relatively benign, and in this study 38 percent of the patients were negative for the serums. This suggests that in the infancy of a disease, the “antibody status” can identify patients "who are likely to have a relatively benign" case of the disease.^[14] The article also emphasizes that these results do not prove that these antibodies are causing the demyelination or apart of a larger process leading to demyelination. One practical application of this experiment and the significance of these results is that currently an MRI has to be used to assess a patient’s risk of developing the first relapse of MS. These results suggest that this cheaper and easier to perform procedure of measuring antibodies has the potential to achieve the same diagnosis.

In a similar study,^[16] the risk conversion for patients diagnosed with clinically isolated syndrome (CIS) to develop clinically definite MS was studied. The anti-myelin antibodies were investigated as the possible predictor for this risk conversion. While 90 percent of CIS patients develop clinically definite multiple sclerosis within so many months to years, the results showed that patients who recorded negatively for antibodies generally have a more favorable prognosis in the delay of this development. Patients who tested positive for antibodies were able to “benefit from early treatment".^[16] Over a 12 month period, 30 patients tested positive for antibodies. 22 of those patients had developed CDMS. Of the patients who tested negative for antibodies, none of them developed CDMS.

In spite of these findings, another study suggests that these studies do not conclusively dictate that MOG is indeed one of the primary contributors in the pathogenic pathway for MS.^[17] MOG has shown the ability to lead to “demyelination in vitro and in experimental animals”. And it has been found both in nerve-tissue lesions, as well as in patients diagnosed with multiple sclerosis. Still, the significance of these findings are not conclusive. Two other studies have only been able to confirm the results presented in the studies mentioned “in a subgroup analysis”. And “three other studies obtained negative results”. This particular study provides an alternative outcome to the given findings by suggesting that this anti-MOG antibody correlation to the development of MS “may at least in part reflect cross-reactivity between MOG and Epstein-Barr nuclear antigen.”^[17][5] With MOG only being synthesized in the CNS, it has become associated with MS. But the true link between MOG and MS is still very controversial, particularly because of the lack of evidence supporting the link between “biologically active anti-MOG antibodies"^[5] and the demyelination that leads to multiple sclerosis. And, while the anti-MOG antibodies are able to be measured in determining the extent of damage in the tissue caused by MS, “apart from biologically active antibodies",^[5] it may be that “antibodies are just a bystander phenomenon of CNS tissue destruction".^[5]

References

External links

• Online 'Mendelian Inheritance in Man' (OMIM) 159465

v d e PDB gallery 1py9: The crystal structure of an autoantigen in multiple sclerosis