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PubMed1986

Are anti-brain antibodies in multiple sclerosis directed to myelin basic protein? Studies employing the Shiverer mouse mutant.

The dysmyelinating mouse mutant Shiverer has a severe and relatively selective deficiency of myelin basic protein (MBP) in the central and peripheral nervous system. Nevertheless, Shiverer brain and control-mouse brain showed similar antigenic titers when tested by a complement fixation assay against a panel of 14 multiple sclerosis (MS) sera and 6 MS CSF samples known to represent several specificities of antibrain antibodies. By analogy with experimental allergic encephalomyelitis, a sensitization to MBP has been proposed in MS. Our results, however, show that antibodies to other CNS antigens are quantitatively more important in this disease.

Animals↗
PubMed1987

The sequence of myelination in the brainstem of the rat monitored by myelin basic protein immunohistochemistry.

The temporal order which is observed by nervous pathways in their myelination was investigated in the brainstem of neonatal to 16-day-old albino rats. The immunohistochemical detection of myelin basic protein in newly forming myelin sheaths provided a highly sensitive and specific criterion to judge the time of onset and the progress of myelination in its initial stages. Immunohistochemistry was performed on paraffin-embedded tissue according to the unlabeled peroxidase-antiperoxidase method. A small number of immunoreactive fibers was already present in neonate rats in the ventral funiculus of the cervical spinal cord and in the medial longitudinal fascicle of the medulla oblongata. By the 4th postnatal day myelination had commenced in many sensory tracts and in the trigeminal root, in the tectospinal tract, in the inferior cerebellar peduncle and in the roots of most cranial motor nerves. The auditory pathway up to the inferior colliculus, the gracile, spinocerebellar and rubrospinal tracts and the superior cerebellar peduncle had acquired some myelin on the 7th day. Phylogenetic late fiber systems also appeared to myelinate comparatively late: the transverse pontine fibers and the medial cerebellar peduncle started on the 10th day, and in the corticospinal tract a conspicuously synchronized myelination appeared on the 13th day. All pathways of the brainstem possessed myelinated fibers on the 16th day and some tracts had approached their relative maturity.

Aging↗
PubMed1991

Insulin-sensitive myelin basic protein phosphorylation on tyrosine residues.

Rat brain plasma membranes were solubilized in detergent and a glycoprotein-enriched fraction was obtained by lectin affinity chromatography. This glycoprotein fraction contained insulin receptors, as well as protein kinases capable of phosphorylating some exogenously added substrates such as MAP2 (microtubule associated protein 2) and MBP (myelin basic protein), but not ribosomal protein S6. Phosphoamino acid analysis of MAP2 and MBP showed that phosphotyrosine residues, as well as phosphoserine/phosphotheronine residues, were present in both proteins under basal conditions. Whereas the addition of insulin to the rat brain membrane glycoprotein fraction in vitro had no effect on MAP2 phosphorylation, MBP phosphorylation was stimulated 2.7-fold in response to insulin. This phenomenon was dose-dependent, with half-maximal stimulation of MBP phosphorylation observed with 2 nM insulin. Phosphoamino acid analysis of MBP indicated that insulin stimulated the phosphorylation of tyrosine residues nearly three-fold, whereas the phosphorylation of serine or threonine residues was not increased. These results identify MBP as a substrate for the rat brain insulin receptor tyrosine-specific protein kinase in vitro.

Adenosine Triphosphate↗
PubMed2003

Expression and properties of the recombinant murine Golli-myelin basic protein isoform J37.

A recombinant form of the murine Golli-myelin basic protein (MBP) isoform J37 (rmJ37) has been expressed in Escherichia coli and isolated to 95% purity via metal chelation and ion exchange chromatography. The protein did not aggregate lipid vesicles containing acidic phospholipids, unlike the 18.5 kDa isoform of MBP. This result is consistent with J37 having a functional role prior to the assembly of compact myelin. Circular dichroic spectroscopy showed that rmJ37 had a large proportion of random coil in aqueous solution but gained alpha-helix and beta-sheet in the presence of monosialoganglioside G(M1) and PI(4)P. Thus, like "classic" MBP, J37 is intrinsically unstructured, and its conformation depends on its environment and bound ligands. Analyses of the amino acid sequence of rmJ37 predicted an N-terminal calmodulin (CaM)-binding site. It was determined via a gel-shift assay and fluorescence spectroscopy that rmJ37 and CaM interacted in a 1:1 ratio in a Ca(2+)-dependent manner. However, the interaction was weak compared with 18.5 kDa MBP.

Animals↗
PubMed1982

Effect of pH and fatty acid chain length on the interaction of myelin basic protein with phosphatidylglycerol.

The basic protein of myelin binds electrostatically to acidic lipids but has several hydrophobic segments which may penetrate into the lipid bilayer. Calorimetric and spin-label evidence suggests that below the phase transition temperature, Tc, several phase states occur in the complex of phosphatidylglycerol with basic protein, possibly due to differences in the degree of penetration of the protein and/or interdigitation of the lipid acyl chains. One of these states is a metastable state which starts to melt 10 degrees C below the Tc of the pure lipid and then refreezes, with release of heat, into a stable state. The stable state melts near the Tc of the pure lipid but restricts the motion of fatty acid spin-labeled near the terminal methyl much more than does the pure lipid. The relationship between the rate of conversion to the stable state and the degree of penetration of the protein at varying pH, in the range 4--8, and the lipid acyl chain length, in the range 14 to 18 carbons, was investigated. Altering the pH in this range affects protonation of the histidines of the protein but has no effect on the lipid at pH 4 and above. The rate of conversion of the sample to both the metastable state and the stable state decreased with increase in pH for phosphatidylglycerol with all lipid chain lengths. It also decreased with decreasing chain length at constant pH. This suggested that the lipid could refreeze into the stable state more readily if a smaller proportion of the total bilayer thickness was occupied by the hydrophobic segments of the protein. The consistency of these results with the concept of penetration of portions of the protein partway into the bilayer lends support to this hypothesis.

Binding Sites↗
PubMed1980

The binding of calmodulin to myelin basic protein and histone H2B.

1. A calmodulin-binding protein of apparent mol.wt. 19 000 has been purified from chicken gizzard. Similar proteins have been isolated from bovine uterus, rabbit skeletal muscle and rabbit liver. 2. These proteins migrated as an equimolar complex with bovine brain calmodulin on electroporesis on polyacrylamide gels in the presence of Ca2+ and 6M-urea. The complex was dissociated in the presence of EGTA. 2. The chicken gizzard calmodulin-binding protein has been shown to be identical with chicken erythrocyte histone H2B on the basis of partial amino acid sequence determination. 4. The calmodulin-binding proteins of apparent mol.wt. 22 000 isolated previously from bovine brain [Grand & Perry (1979) Biochem. J. 183, 285-295] has been shown, on the basis of partial amino-acid-sequence determination, to be identical with myelin basic protein. 5. The activation of bovine brain phosphodiesterase by calmodulin is inhibited by excess bovine uterus calmodulin-binding protein (histone H2B). 6. The phosphorylation of myelin basic protein by phosphorylase kinase is partially inhibited, whereas the phosphorylation of uterus calmodulin-binding protein (histone H2B) is unaffected by calmodulin or troponin C. 7. The subcellular distribution of myelin basic protein and calmodulin suggests that the two proteins do not exist as a complex in vivo.

Amino Acid Sequence↗
PubMed1997

Three-dimensional structure of myelin basic protein. I. Reconstruction via angular reconstitution of randomly oriented single particles.

Myelin basic protein (MBP) plays an integral role in the structure and function of the myelin sheath. In humans and cattle, an 18.5-kDa isoform of MBP predominates and exists as a multitude of charge isomers resulting from extensive and varied post-translational modifications. We have purified the least modified isomer (named C1) of the 18.5-kDa isoform of MBP from fresh bovine brain and imaged this protein as negatively stained single particles adsorbed to a lipid monolayer. Under these conditions, MBP/C1 presented diverse projections whose relative orientations were determined using an iterative quaternion-assisted angular reconstitution scheme. In different buffers, one with a low salt and the other with a high salt concentration, the conformation of the protein was slightly different. In low salt buffer, the three-dimensional reconstruction, solved to a resolution of 4 nm, had an overall "C" shape of outer radius 5.5 nm, inner radius 3 nm, overall circumference 15 nm, and height 4.7 nm. The three-dimensional reconstruction of the protein in high salt buffer, solved to a resolution of 2.8 nm, was essentially the same in terms of overall dimensions but had a somewhat more compact architecture. These results are the first structures achieved directly for this unusual macromolecule, which plays a key role in the development of multiple sclerosis.

Animals↗
PubMed1989

A mitogen for Schwann cells is derived from myelin basic protein.

Evidence is presented that a mitogen can be produced from myelin basic protein (MBP) which may be related to the Schwann cell proliferation characteristic of Wallerian degeneration. Myelin derived from the shiverer mutant which is devoid of MBP is also devoid of mitogenic activity. Absorption of the mitogen with a polyclonal antisera to MBP abolishes the mitogenic effect. In addition, only liposomes containing MBP are mitogenic to cultured Schwann cells; liposomes containing other myelin-specific proteins do not stimulate Schwann cell division. These results directly demonstrate the MBP origin of a mitogen for Schwann cells.

Animals↗
PubMed1977

Experimental allergic encephalomyelitis in the Lewis rat: farther delineation of active sites in guinea pig and bovine myelin basic proteins.

Highly encephalitogenic peptide (37-88), derived from the guinea pig myelin basic protein by peptic digestion, was treated chemically to destroy its tyrosyl and histidyl residues and enzymatically to remove its C-terminal sequence Val-His-Phe. Neither of the modifications resulted in loss of activity in Lewis rats. The enccephalitogenic region within peptide (37-88) was located by examination of derivative peptides obtained by selective proteolytic cleavage. The results showed that peptide (61-88), like peptide (43-88), was fully active at the level of 0.02 nmole whereas peptides (72-88) and (72-84) were fully active at levels of 0.5 and 2.5 nmole, respectively. In contrast, peptides (43-71) and (75-88) were completely inactive. These results demonstrated that the undecapeptide Gln-Lys-Ser-Gln-Arg-Ser-Gln-Asp-Glu-Asn-Pro (residues 72-84), although not as encephalitogenic as peptides (43-88) or (61-88), does contain the elements essential for the induction of disease. At the levels tested (10.8 and 2.2 nmole) only peptides (43-88) and (61-88) were capable of inhibiting the induciton of disease by passively transferred lymph node cells; this inhibition, however, was less than that achieved by the intact guinea pig basic protein. Further studies on the encephalitogenicity of the bovine basic protein in Lewis rats demonstrated that the active site in the C-terminal half of this protein is present in its entirety within residues 89 to 115.

Amino Acid Sequence↗
PubMed1975

The development of experimental allergic encephalomyelitis with immunizing doses of myelin basic protein.

Rabbits immunized with low (11.25 mg) and high (57.50 mg) doses of myelin basic protein from several species develop antibasic protein antibodies, delayed type hypersensitivity, and clinical and pathological signs of experimental allergic encephalomyelitis. More than 55% of rabbits immunized with relatively high doses of basic protein develop disease. The absence of circulating antibasic protein antibodies in immunorespondent animals is associated with the appearance of clinical or histological signs of experimental allergic encephalomyelitis; however, the presence of humoral antibodies did not prevent completely the development of disease. Delayed-type hypersensitivity, specific for the basic protein, appears as early as 5 days after immunization and is maintained in nondiseased and surviving animals. Neither excess encephalitogen nor encephalitogen-induced antibody is sufficient to suppress completely the eventual development of clinical or histological manifestations of disease.

Animals↗
PubMed1989

Limited proteolysis of bovine myelin basic protein by calcium-dependent proteinase from bovine spinal cord.

In order to shed some light on the role of proteinases in the process of demyelination in the central nervous system, a calcium-dependent proteinase was purified to homogeneity from bovine spinal cord, and its action on myelin basic protein purified from the same tissue was investigated. Among the three major myelin basic protein fractions, Fraction I was resistant to the action of the enzyme whereas Fractions II and III were degraded in the same manner, giving two major bands on SDS-polyacrylamide gel electrophoresis. The hydrolysis products were fractionated by high-performance liquid chromatography and characterized. The results showed that the myelin basic protein (Fractions II and III) was rather selectively cleaved at the Val93-Thr94 bond and the Arg96-Thr97 bond in mutually exclusive ways, with minor cleavages at the Ala16-Ser17 and Gly68-Ser69 bonds, suggesting the implication in vivo of calcium-dependent proteinase in the limited proteolysis of myelin basic protein.

Animals↗
PubMed2001

Distinct molecular mechanisms lead to diminished myelin basic protein and 2',3'-cyclic nucleotide 3'-phosphodiesterase in qk(v) dysmyelination.

The genetic lesion of quakingviable (qk(v)) causes diminished expression of the QKI RNA-binding protein in myelin producing cells. Consequently, several structural myelin proteins are severely reduced. Among these affected proteins, the reduction of the myelin basic protein (MBP) results from post-transcriptional abnormalities of the MBP mRNA, presumably due to the lack of interactions with QKI. However, whether this is the common mechanism for reduced expression of other myelin proteins in qk(v) dysmyelination remains unclear. Here we report that distinct molecular mechanisms underlie the reduction of MBP and the 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) in qk(v) dysmyelination. MBP transcripts bind QKI strongly and are markedly reduced in the qk(v)/qk(v) oligodendrocytes in which QKI is almost completely lost. In contrast, CNP transcripts bind QKI weakly and are only slightly affected by the lack of QKI. None the less, CNP proteins are severely reduced in the qk(v)/qk(v) brain. Since CNP transcripts are predominantly associated with translating polyribosomes, diminished CNP expression in qk(v) dysmyelination is unlikely to be due to translational failures, but more likely results from accelerated protein degradation.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗
PubMed1996

Myelin basic protein in experimental allergic encephalomyelitis is not affected at the posttranslational level: implications for demyelinating disease.

The microheterogeneity of myelin basic protein, expressed as the ratio between the least cationic (C-8) charge isomer and the most cationic (C-1), was examined in experimental allergic encephalomyelitis (EAE) cases. These included acute EAE of 2 months' duration induced with bovine proteolipid protein in complete Freund's adjuvant (CFA), chronic EAE induced with mouse spinal cord homogenate in varying doses from 0.5 to 2.0 mg in CFA, and chronic relapsing EAE of 12 months' duration induced with synthetic peptide 139-151 of the proteolipid protein sequence. The C-8/C-1 ratio was within the normal range for all groups of animals. However, the C-8/C-1 ratio was six- to sevenfold increased in a spontaneously demyelinating transgenic model, ND4, which contains 70 copies of the cDNA for DM20 (Mastronardi et al.: 1996). Since an increase in the C-8/C-1 ratio was also observed in victims of multiple sclerosis but not other neurological diseases, the ND4 model may address primary changes prior to demyelination, while the EAE model addresses the autoimmune aspects of the disease.

Animals↗
PubMed1991

A single amino acid change in a myelin basic protein peptide confers the capacity to prevent rather than induce experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is an experimental demyelinating disease of rodents. In (PL/J x SJL) F1 mice, it is induced by immunization with the myelin basic protein peptide Ac1-11. Ac1-11 [4A], a myelin basic protein peptide analog with a single amino acid substitution, (i) binds to class II major histocompatibility complex molecules and stimulates encephalitogenic T cells in vitro better than Ac1-11, (ii) is nonimmunogenic and nonencephalitogenic in vivo in (PL/J x SJL)F1 mice, (iii) prevents EAE when administered before or at the time of immunization with Ac1-11, and (iv) prevents EAE when administered later, near the time of disease onset. Initial studies suggest that Ac1-11 [4A] does not prevent EAE by competitive inhibition or by activation of regulatory cells. Thus, substitution of a single amino acid in a myelin basic protein peptide confers the capacity to prevent rather than induce EAE, even after peptide-specific encephalitogenic T cells have been activated.

Amino Acid Sequence↗
PubMed1993

Myelin basic protein mRNA translocation in oligodendrocytes is inhibited by astrocytes in vitro.

Myelin basic protein (MBP) mRNAs are translocated from cell bodies into the slender processes connecting oligodendrocyte somas with the myelin sheath in vivo. This translocation was observed in mixed glial cultures prepared from newborn mouse brains and it occurred in approximately 25% of the cells expressing the gene. However, when "enriched" oligodendrocytes were prepared by shaking them free of other glial cells, MBP mRNA translocation occurred into the processes of essentially all of the cells. When enriched oligodendrocytes were plated back onto astrocytes, MBP mRNA was observed to be confined to the cell bodies of almost all the cells, indicating a marked inhibition of translocation of the mRNA. This inhibition of mRNA translocation did not appear to be mediated through soluble factors secreted by astrocytes or by "astromatrix," but rather through physical contact between the oligodendrocytes and astrocytes. Intact, but not necessarily live, astrocytes were required for the inhibition of mRNA translocation in the oligodendrocytes. Fibroblasts and a neuroblastoma cell line, SKN-SH, did not inhibit MBP mRNA translocation in oligodendrocytes suggesting that astrocyte surface-specific components might be involved in the interaction between astrocytes and oligodendrocytes in culture. These results suggest that contact between these two cell types can influence intramolecular events related to myelinogenesis.

Animals↗
PubMedDate not supplied

Hyperreactivity to myelin basic protein in multiple sclerosis.

Multiple sclerosis patients, control patients with other neurological diseases, and normal volunteers were assayed in a short-term 51chromium release assay for cell-mediated cytotoxicity against lymphocyte targets coated with myelin basic protein. Multiple sclerosis patients, compared to the other two groups, were hyperreactive to myelin basic protein, both before and after in vitro boost with additional myelin basic protein. The boost served to augment the difference between multiple sclerosis patients and controls.

Cytotoxicity, Immunologic↗
PubMed1991

Fetal alcohol delays the developmental expression of myelin basic protein and transferrin in rat primary oligodendrocyte cultures.

This study has examined the development of immunoreactive myelin basic protein and transferrin in primary glial cell cultures. Cultures were initiated from control and experimental Sprague-Dawley rats 1-2 days postnatally. Experimental treatment involved exposure to 5% (w/v) ethanol in a liquid diet during the last two weeks of gestation. Prenatal alcohol administration delayed the expression of myelin basic protein and transferrin during the first three weeks postnatally. Other oligodendroglial and astroglial markers were little affected, if at all, by fetal alcohol exposure.

Animals↗