Myelin oligodendrocyte glycoprotein
|Myelin oligodendrocyte glycoprotein|
Crystal structure of rat myelin oligodendrocyte glycoprotein.
|Symbols||MOG (; MOGIG2; NRCLP7)|
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. 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.
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”. 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.”
MOG’s cDNA coding region in humans have been shown to be “highly homologous” to rats, mice, and bovine, and hence highly conserved. This suggests “an important biological role for this protein”.
The gene for MOG, found on chromosome 6p21.3-p22, 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, 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 easily accessible for autoantibodies. 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 reptitive DNA" sequences, among which is "14 Alu sequences within 3 introns", and have a range varying from 242 to 6484 bp.
Because of alternatively spliced from human mRNA of MOG gene forming at least nine isoforms.
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. The dssp secondary structure of the protein is 6% helical and 43% beta sheet: there are three short helical segments and ten beta strands. The beta strands are within two antiparallel beta sheets that form an immunoglobulin-like beta-sandwich fold. 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."
Developmentally, MOG is formed "very late on oligodendrocytes and the myelin sheath".
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. 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. Animal models of MS, EAE, have shown that “MOG-specific EAE models (of different animal strains) display/mirror human multiple sclerosis", 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”.
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”. 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. The other is myelin oligodendrocyte glycoproteins (MOG). Both "have been identified as targets of the immune response". 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.
In one particular study, the presence of anti-MOG and anti-MBP antibodies in patients' blood sera was correlated with an MS relapse among people with a "clinically isolated syndrome," converting their diagnosis to "clinically definite". Only 23% of the patients who tested seronegative for both antibodies relapsed, after 45.1±13.7 months. In contrast, 83% of the patients with only the anti-MOG antibody had a relapsed after 14.6±9.6 months. All but one of the 22 patients who had both antibodies relapsed after 7.5 ± 4.4 months.
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 antibodies. 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. The article also emphasizes that these results do not prove that the antibodies cause demyelination, but that they are a useful diagnostic indicator of disease progression. One practical application of this study is that the method provides a cheaper and easier alternative to the current strategy of using MRI imaging to assess a patient’s risk of relapsing into MS from a "clinically isolated" diagnosis.
In a similar study, 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". 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. 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.” 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" 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", it may be that “antibodies are just a bystander phenomenon of CNS tissue destruction".
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