Myelin oligodendrocyte glycoprotein
Encyclopedia
Myelin Oligodendrocyte Glycoprotein (MOG) is a glycoprotein
believed to be important in the process of myelin
ization of nerve
s 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.
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”.
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.
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."
, vanishing white matter disease
, and multiple sclerosis
(MS). 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”.
, leading to demyelination. In this theory, target antigen
s 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 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.
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. 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, 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”.
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
believed to be important in the process of myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
ization of nerve
Nerve
A peripheral nerve, or simply nerve, is an enclosed, cable-like bundle of peripheral axons . A nerve provides a common pathway for the electrochemical nerve impulses that are transmitted along each of the axons. Nerves are found only in the peripheral nervous system...
s in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS). In humans this protein is encoded by the MOG gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. 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”. 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”.
Physiology
The gene for MOG, found on chromosome 6p21.3-p22, was first sequenced in 1995. It is a transmembrane proteinTransmembrane protein
A transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...
expressed
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
on the surface of oligodendrocyte cell
Oligodendrocyte
Oligodendrocytes , or oligodendroglia , are a type of brain cell. They are a variety of neuroglia. Their main function is the insulation of axons in the central nervous system of some vertebrates...
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.
Structure
Because of alternatively spliced from human mRNA of MOG gene forming at least nine isoforms. Boyle, L.H., Traherne, J.A., Plotnek, G et Splice variation in the cytoplasmic domains of myelin oligodendrocyte glycoprotein affects its cellular localisation and transport. Journal of Neurochemistry, 2007, 102, 1853-62.”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."
Synthesis
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 adrenoleukodystrophyAdrenoleukodystrophy
Adrenoleukodystrophy is a rare, inherited disorder that leads to progressive brain damage, failure of the adrenal glands and eventually death. ALD is a disease in a group of genetic disorders called leukodystrophies, whose chief feature is damage to myelin...
, vanishing white matter disease
Leukoencephalopathy with vanishing white matter
Leukoencephalopathy with vanishing white matter is an autosomal recessive neurological disease. The cause of the disease are mutations in any of the 5 genes encoding subunits of the translation initiation factor EIF-2B: EIF2B1, EIF2B2, EIF2B3, EIF2B4, or EIF2B5...
, and multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
(MS). It is a target antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
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
Pathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...
of MS.
Animal models of MS, EAE
Experimental autoimmune encephalomyelitis
Experimental autoimmune encephalomyelitis, sometimes Experimental Allergic Encephalomyelitis is an animal model of brain inflammation. It is an inflammatory demyelinating disease of the central nervous system...
, 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
Topography
Topography is the study of Earth's surface shape and features or those ofplanets, moons, and asteroids...
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”.
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 systemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
, leading to demyelination. In this theory, target antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s 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
Myelin basic protein
Myelin basic protein is a protein believed to be important in the process of myelination of nerves in the central nervous system .MBP was initially sequenced in 1971 after isolation from myelin membranes...
(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 experiment calls for serums of anti-MOG and anti-MBP to test their tendencies on causing conversion of a "clinically isolated syndrome
Clinically isolated syndrome
A clinically isolated syndrome is an individual's first neurological episode, caused by inflammation or demyelination of nerve tissue...
" 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.
Given the results, a patient with a “clinically isolated syndrome
Clinically isolated syndrome
A clinically isolated syndrome is an individual's first neurological episode, caused by inflammation or demyelination of nerve tissue...
” 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. 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, 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
Epstein-Barr virus nuclear antigen (EBNA) IRES
This family represents an Epstein-Barr virus internal ribosome entry site which is found in the U leader exon in the 5' UTR of the Epstein-Barr nuclear antigen 1 gene. The EBNA IRES allows EBNA1 translation to occur under situations where initiation from the 5' cap structure and ribosome scanning...
.”
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”.