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Results for “Myelin Basic Protein”

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PubMed1986

Regulation of myelin basic protein in oligodendrocytes by a soluble neuronal factor.

Myelin basic protein (MBP) is one of the most important myelin components. Based on our previous studies, we hypothesized that neurons might have regulatory effects on the production of MBP by oligodendrocytes, and we conducted studies designed to verify this hypothesis. Oligodendroglia-rich cultures from total brain of neonatal rats or mice and pure cultures of embryonic rats or chicks were prepared. Cultures of mouse fibroblasts and astrocytes were prepared as well. We show here that MBP production by oligodendrocytes was greatly enhanced by treatment with either pure neurons, rat neuronal conditioned medium, or chick neuronal conditioned medium, while chemically defined, hormonally supplemented medium or medium conditioned by astrocytes and fibroblasts had no effect on MBP expression. We conclude that the production of MBP by oligodendrocytes is regulated by a nonspecies specific soluble neuronal factor. The conservation of this phenomenon from avian to rodent species implies its critical role in myelination and suggests its potential application as a treatment in demyelination.

Animals↗

PubMed2003

Thr94 in bovine myelin basic protein is a second phosphorylation site for 42-kDa mitogen-activated protein kinase (ERK2).

Treatment of bovine brain myelin basic protein with 42-kDa mitogen-activated protein kinase [p42 MAPK or extracellular signal-regulated kinase 2 (ERK2)] in the presence of ATP and Mg2+ results in phosphorylation of Thr94 and Thr97. Thr94 is not previously known to be an ERK2 phosphorylation site. Both residues are phosphorylated to about the same extent and are in the highly conserved segment Asn91-Ile-Val-Thr94-Pro-Arg-Thr97-Pro-Pro-Pro-Ser101 MALDI mass spectrometry before and after ERK2 treatment revealed the addition of two phosphate groups to the protein. Tryptic cleavage resulted in a single fragment (positions 91-104) carrying the observed mass increase. Tandem mass spectrometry applied to the tryptic peptide showed that both Thr94 and Thr97 are acceptors of phosphate. A singly phosphorylated species could not be detected. Identification of the ERK2 phosphorylation site Thr94 in bovine myelin basic protein reveals a nontraditional phosphate acceptor position, preceded by three noncharged residues (Asn-Ile-Val). Proline at position -2 or -3 from the phosphorylation site, typical for the recognition sequence of proline-directed kinases, is missing. The results provide information for delineation of a further substrate consensus motif for ERK2 phosphorylation.

Animals↗

PubMed2006

Endogenous myelin basic protein is presented in the periphery by both dendritic cells and resting B cells with different functional consequences.

Multiple sclerosis is an inflammatory disease believed to be triggered by erroneous activation of self-reactive T cells specific for myelin proteins such as myelin basic protein (MBP). Inflammation is limited to the CNS, suggesting that the myelin-specific T cells encounter their Ags only after they cross the blood-brain barrier. However, our previous studies in mice showed that MBP epitopes are constitutively presented in lymphoid tissues. Here we identified which APCs in lymph nodes present endogenous MBP epitopes and determined the functional consequences of this presentation for both naive and activated MBP-specific T cells. Both CD8alpha+ and CD8alpha- dendritic cells were potent stimulators of proliferation for both naive and previously activated/memory MBP-specific T cells. Surprisingly, resting B cells also presented endogenous MBP that was acquired using a BCR-independent mechanism. Interaction with resting B cells triggered proliferation of both naive and activated MBP-specific T cells. Activated/memory MBP-specific T cells proliferating in response to resting B cells presenting endogenous MBP did not produce cytokines and became more refractory to subsequent stimulation. Interestingly, cytokine production by activated/memory T cells was triggered by resting B cells if the number of MBP epitopes presented was increased by adding exogenous MBP peptide. These results suggest that activated MBP-specific T cells may become less pathogenic in vivo following encounter with resting B cells presenting steady-state levels of endogenous MBP but can expand and remain pathogenic if the amount of MBP presented by B cells is increased, which could occur during chronic demyelinating disease.

Animals↗

PubMed1982

[Determination of myelin basic protein in the cerebrospinal fluid in neurologic diseases].

Myelin basic protein (BP) is a specific constituent of the myelin sheath. This structural protein cannot be detected in the cerebrospinal fluid (CSF) unless myelin is acutely degraded. In order to detect active demyelinating diseases, BP was measured in CSF samples of radioimmunoassay. The assay is specific and sensitive to as little as 1.5 to 2.5 ng/ml BP. A moderate non-parallelism between the standard curve and various dilutions of CSF samples indicates that in CSF BP is present in an altered state. Over 1000 CSF samples have been measured in a double-blind study, in which 100 patients were selected and their clinical records evaluated. Twenty-eight patients without demyelinating disease had BP levels lower than 2.5 ng/ml. 72 patients had values higher than 2.5 ng/ml. Among them, the most frequent causes of demyelination were multiple sclerosis (19 cases), brain tumors (22 cases) and cerebral or spinal vascular accidents (12 cases). During a single acute demyelinating episode, BP levels revert to background levels within a few days. In contrast to immunological anomalies observed in the CSF, the presence of BP is concomitant with the breakdown of myelin. The size and location of the lesion influence the level of BP in the CSF. Thus, the assay is useful for the detection of active demyelination in the central nervous system and in following the course of the disease, although normal values do not rule out the presence of demyelinating lesions. For the time being, therefore, this assay should be restricted to specialized neurological centers and selected patients.

Adult↗

PubMed1977

[Pathogenesis of multiple sclerosis. Antibody dependent cytotoxicity of lymphocytes against myelin basic proteins in multiple sclerosis].

In 79 of 100 patients with multiple sclerosis, serum antibodies of the IgG type were demonstrated which render normal lymphocytes cytotoxic against basic protein of myelin. In 11 cerebrospinal fluids which were tested the antibody was also found. The method used was the release of 51Cr from chicken erythrocytes coated with antigen. The antibody-dependent lymphocyte cytotoxicity is related to the degree of activity of the disease and not to the evolution of the disease or its course. As the disease worsens, the frequency of positive reactions is higher than in inactive stages. The immunological reaction is very specific for multiple sclerosis, in patients with other neurological disorders only 5% had positive findings. The antibody-dependent cytotoxicity of lymphocytes against basic protein of myelin may be attributed with a certain diagnostic significance. The reaction seems suitable for the supervision of the course of multiple sclerosis and to check the effect of therapeutic measures. The antibody-dependent lymphocyte cytotoxicity against basic protein of myelin is considered to be significant in the pathogenesis of multiple sclerosis.

Antibody-Dependent Cell Cytotoxicity↗

PubMed1984

Phospholipid-sensitive Ca2+ -dependent protein kinase preferentially phosphorylates serine-115 of bovine myelin basic protein.

Phospholipid-sensitive Ca2+ -dependent protein kinase (PL-Ca-PK) and cyclic AMP-dependent protein kinase (A-PK) both preferentially phosphorylated serine residues of bovine myelin basic protein (MBP). Tryptic peptide maps of MBP phosphorylated by PL-Ca-PK or A-PK, however, revealed different phosphopeptides, suggesting a difference in the intramolecular substrate specificity for the two enzymes. Serine-115 of MBP, in the sequence (-Arg-Phe-Ser(115)-Trp-), was found to be a preferred and probably major phosphorylation site for PL-Ca-PK. Because serine-115 of bovine MBP corresponds to serine-113 of rabbit MBP, an in vivo phosphorylation site reported by Martenson et al. (1983), and PL-Ca-PK is present at a very high level in brain and myelin, it is suggested that the enzyme may be responsible for the in vivo phosphorylation of this and other sites in MBP.

Amino Acid Sequence↗

PubMed1993

Neuroanatomical localization of myelin basic protein in the late first and early second trimester human foetal spinal cord and brainstem.

The temporal and spatial expression of myelin basic protein in the first and second trimester human foetal spinal cord and brainstem from 9 to 20 gestational weeks was determined by immunocytochemistry in sections of cervical, thoracic and lumbosacral levels from 41 human foetal spinal cords and ten brainstems. Myelin basic protein-positive oligodendrocytes were observed peripheral to the ependyma at 9-10 gestational weeks. Oligodendrocytes expressing myelin basic protein were seen at 10-12 gestational weeks in the anterior and lateral funiculi. Myelin basic protein was detected later in the posterior funiculi than in the anterolateral white matter and most spinal cord tracts could not be identified by means of variation in myelin basic protein expression. Myelin basic protein was found in the midline of the brainstem at ten gestational weeks and spread laterally during the second trimester. We conclude that in the human foetal spinal cord, myelin basic protein is present by 10 gestational weeks in the anterolateral cervical spinal cord and midline of the brainstem. It is expressed in a rostral-to-caudal and anterolateral-to-posterior manner in most tracts of the spinal cord. However, an exception to these findings is that the fasciculus gracilis, upon developing into a defined region, had more myelin basic protein-positive cells at the lumbar level than in more rostral regions. Definition of the kinetics of myelin basic protein expression in the normal human foetal spinal cord provides a baseline for study of aberrant myelination and demyelination.

Brain Chemistry↗

PubMed1993

Staurosporine activates a 60,000 M(r) protein kinase in bovine chromaffin cells that phosphorylates myelin basic protein in vitro.

Bovine chromaffin cells contain a family of renaturable protein kinases. One of these, a 60,000 M(r) kinase (PK60) that phosphorylated myelin basic protein in vitro, was activated fourfold when cells were treated with the protein kinase inhibitor staurosporine. Because staurosporine inhibits protein kinase C, the role of this kinase in the regulation of PK60 activity was investigated. Fifty nanomolar staurosporine produced half-maximal inhibition of protein kinase C activity in chromaffin cells, whereas approximately 225 nM staurosporine was required to induce half-maximal activation of PK60. Other protein kinase C inhibitors, H-7 and K-252a, did not mimic the effect of staurosporine on PK60 activity. Chromaffin cells have three protein kinase C isoforms: alpha, epsilon, and zeta. Prolonged treatment with phorbol esters depleted the cells of protein kinase C alpha and epsilon, but not zeta. Neither activation nor depletion of protein kinase C affected the basal activity of PK60. Moreover, staurosporine activated PK60 in cells depleted of protein kinase C alpha and epsilon; thus, staurosporine appeared to activate PK60 by a mechanism that does not require these protein kinase C isoforms. Incubation of cell extracts with staurosporine in vitro did not activate PK60. Incubation of these extracts with adenosine 5'-O-(3-thiotriphosphate), however, caused a twofold activation of PK60. Although this suggests that PK60 activity is regulated by phosphorylation, the mechanism by which staurosporine activates PK60 is not known. Staurosporine has been reported to promote neurite outgrowth from chromaffin cells. The role of PK60 in mediating the effects of staurosporine on chromaffin cell function remains to be determined.

Adenosine Triphosphate↗

PubMed1996

Transcription of myelin basic protein promoted by regulatory elements in the proximal 5' sequence requires myelinogenesis.

Myelination in the central nervous system requires synthesis by oligodendrocytes of enormous amounts of lipids and proteins for incorporation in the developing myelin membranes. To approach the regulatory events coordinating the transcriptional activation of the genes that encode myelin proteins, we examined control of the myelin basic protein (MBP) locus. MBP plays a major role in myelin compaction. During development, MBP is already expressed in mature non-myelinating oligodendrocytes. Here we show that, in transgenic animals in which the E. coli lacZ reporter gene is under the control of increasingly large portions (256, 1900 and 3200 bp) of the MBP promoter, 5' of the initiation of transcription site, reporter gene expression was initiated after myelin formation had started. This delayed expression of the transgene compared to MBP, strongly suggests that premyelinating expression is dependent on regulatory elements located outside of the 3200 bp sequence studied, while expression occurring at the time of myelin formation is dependent on the proximal promoter sequence.

Animals↗

PubMed1991

Fluorescence studies on the interactions of myelin basic protein in electrolyte solutions.

This paper examines the influence of electrolytes on fluorescence spectral properties of the single tryptophanyl residue, Trp-115, within the 18.5-kDa species of myelin basic protein from bovine brain. Steady-state fluorescence spectra and intensities and time-correlated fluorescence lifetimes increased in the presence of increasing concentrations of mono- and divalent electrolytes (Li+, Na+, K+, Mg2+, Ca2+, Cl-, ClO4-, SO4(2-), and PO4(3-)). In all cases, the increases closely paralleled the ionic strength of the bulk aqueous medium and resembled that observed upon immersion of the protein in solutions of urea. This behavior was therefore concluded to reflect changes in the solution conformation of myelin basic protein. Bimolecular quenching of Trp-115 by acrylamide was rapid (10(9) M-1 s-1), approaching the diffusion limitation, and markedly dependent on the viscosity of the bulk aqueous medium. Rotational depolarization of myelin basic protein was rapid (phi less than or equal to 1 ns), occurring at rates exceeding those predicted for a rigid particle of revolution, and markedly dependent on the viscosity of the surrounding medium. Whereas the bimolecular quenching constants were unaltered in the presence of electrolytes, rotational depolarization of myelin basic protein underwent substantial slowing as indicated by the appearance of an additional decay component characterized by a correlation time of 5-10 ns. These studies indicate that Trp-115 of myelin basic protein is readily accessible to the bulk aqueous medium and is associated with a highly mobile segment of the protein. The slowing of rotational depolarization upon immersion of myelin basic protein in electrolyte solutions is consistent with an electrolyte-induced self-association of myelin basic protein molecules and indicates a relationship between the lability of solution conformation on the one hand and the capacity for self-association on the other.

Acrylamide↗

PubMed2001

Myelin basic protein is necessary for the regulation of myelin-associated glycoprotein expression in mouse oligodendroglia.

Myelin-associated glycoprotein (MAG) has currently been proposed to be a possible igniter of myelination in the central nervous system. We propose here that myelin basic protein (MBP) is prerequisite, which is more diffusely expressed than MAG in early stages of myelination. MBP-deficient mice show significant reduction of MAG-positive immature oligodendroglia at early stages of myelination, although significant increase of such cells is noted in the adult. MBP/Fyn-double deficient adult mice also show moderate increase of the same type of immature glia, but to a lesser degree than MBP-deficiency alone. The present study suggests that MBP is required for the regulation of MAG expression in oligodendroglia, involving Fyn therein. We discuss the possibility that hitherto unknown molecule, not MAG, may be in responsible for the ignition of the myelination.

Animals↗

PubMed1991

Lipid-protein and protein-protein interactions in double recombinants of myelin proteolipid apoprotein and myelin basic protein with dimyristoylphosphatidylglycerol.

The integral proteolipid apoprotein (PLP) from bovine spinal cord has been reconstituted in dimyristoylphosphatidylglycerol (DMPG) bilayers, and the mutual interactions on binding the peripheral myelin basic protein (MBP) have been studied. Quantitation of protein and lipid contents in the MBP-PLP-DMPG double recombinants at different PLP:DMPG ratios led to the conclusion that MBP binds only to the DMPG lipid headgroups and is hindered from interaction with the first shell of lipids surrounding the PLP. No specific PLP-MBP association could be detected. Electron spin resonance (ESR) spectra of phosphatidylglycerol spin-labeled at position n = 5 in the sn-2 chain showed that complexation of MBP with the PLP-DMPG recombinants leads to a decrease in lipid chain mobility to an extent which correlates with the degree of MBP binding. At low DMPG:PLP ratios, the perturbations of lipid mobility by both proteins are mutually enhanced. In single recombinants of PLP with DMPG, the ESR spectra of phosphatidylglycerol spin-labeled at position n = 14 in the sn-2 chain indicated that approximately 10 lipids/protein are motionally restricted by direct contact with the intramembranous surface of the protein. This number is in agreement with earlier results for reconstitutions of PLP in dimyristoylphosphatidylcholine (DMPC) [Brophy, P. J., Horváth, L. I., & Marsh, D. (1984) Biochemistry 23, 860-865] and is consistent with a hexameric arrangement of the PLP molecules in DMPG bilayers.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1984

Cleavage of myelin basic protein by neutral protease activity of human white matter and myelin.

Polypeptides arising from neutral in vitro proteolysis of myelin basic protein (MBP) of human brain were evaluated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. At pH 7 a marked breakdown of MBP resulted in the formation of 8-12 polypeptides ranging from 6 to 17 kd in molecular weight. As neutral proteolytic activity was not eliminated by either gel filtration or cation-exchange chromatography acid-soluble protease(s) involved probably have a size and electric charge similar to that of MBP. The enzymatic nature of neutral proteolysis was ascertained by heat inactivation and inhibition by alpha 2-macroglobulin. Incomplete inhibition of proteolysis and the failure of small peptides (less than 6 kd) to show up on electrophoresis seem to suggest that MBP was degraded by exopeptic proteases as well. Acid extracts of purified myelin yielded polypeptides similar to those of MBP of delipidated white matter. The results are consistent with a sequential limited proteolysis of MBP by neutral proteases probably associated with myelin and possibly related to the in situ catabolism of MBP in man.

Brain↗

PubMed1993

Phosphorylation sites of myelin basic protein by a catalytic fragment of non-receptor type protein-tyrosine kinase p72syk and comparison with those by insulin receptor kinase.

Myelin basic protein has been used as a model substrate for determination of substrate recognition motif of various protein kinases. In this report phosphorylated sites of bovine brain myelin basic protein were studied with a catalytic fragment of protein-tyrosine kinase p72syk. Three of four tyrosine residues in myelin basic protein were phosphorylated by this kinase. Major phosphorylated site was 134Y and minor phosphorylated sites were 68Y and 127Y. As the phosphorylation site by p56lck was only 68Y, the recognition motif of p72syk was quite different from that of p56lck. Furthermore, the fact that elution pattern on HPLC of the phosphopeptides obtained by insulin receptor kinase was different from that by p72syk suggested that the recognition motif of p72syk was also different from that of insulin receptor kinase. These results may suggest that each protein-tyrosine kinase has a specific substrate recognition motif.

Amino Acid Sequence↗

PubMed1985

The role of charge microheterogeneity of human myelin basic protein in the formation of phosphatidylglycerol multilayers.

Human myelin basic protein (HBP) was fractionated into its various charge isomers by chromatography on CM-52 columns at pH 10.6. Components 1,2,3 and "8" (C-1, C-2, C-3, and C-"8") were cleanly separated. Each component was combined with phosphatidylglycerol (PG) vesicles, at neutral pH at a concentration of 30% (w/w), protein/lipid. C-1, the most cationic of the components was the most effective at inducing the formation of multilayers when studied by liquid X-ray diffraction. C-3, which differs from C-1 by 2 positive charges was less effective than C-2. C-"8" was totally ineffective since the scattering pattern with this component was no different from that of the pure lipid. Thus a seemingly small change in net charge of the protein had a dramatic effect on the ability of the protein to organize the lipid into a crystalline, multilayer arrangement characteristic of compact myelin.

Chromatography↗

PubMed1986

The interaction of myelin basic protein with tubulin and the inhibition of tubulin carboxypeptidase activity.

Tubulin carboxypeptidase was found to be inhibited by myelin basic protein in a concentration dependent manner. The inhibition was produced by the interaction between myelin basic protein with the substrate. As a consequence of this interaction, turbid insoluble aggregates were formed at either 5 degrees or 37 degrees C. The turbidity increased by increasing the myelin basic protein concentration and it reached a plateau at a molar ratio of myelin basic protein to tubulin dimer of about 6. At plateau, the molar ration in the insoluble aggregates was about 6. When tubulin was in excess, the formation of the insoluble aggregates was diminished. However, if the excess of tubulin was added after the formation of the aggregates, the turbidity was not significantly affected. Turbidity was diminished by increasing the ionic strength.

Animals↗

PubMed1982

In vivo incorporation of [32P]orthophosphate into myelin basic protein of developing rabbit brain: its location in components 3 and 5 and in a new protein tentatively identified as basic protein component 7.

Myelin was isolated from the brains of 16-day-old rabbits that had received intracerebral injections of [32P]orthophosphate 24 h earlier. The basic protein was extracted and examined by polyacrylamide gel electrophoresis both at low and at high pH. At low pH a single band corresponding to the basic protein contained all of the covalently bound protein radioactivity. At high pH, three bands of radioactivity corresponding to basic protein components 3, 5, and 7 were observed. Estimation of the specific radioactivities of the components in conjunction with their high pH electrophoretic mobilities indicated that components 3, 5, and 7 contained one, two, and three phosphate groups per molecule of protein, respectively.

Animals↗

PubMed1991

Molecular biology of myelin basic protein: gene rearrangement and expression of anti-sense RNA in myelin-deficient mutants.

1. Myelin is an important structure for facilitating the conduction of impulses along the axons both in the central nervous system (CNS) and peripheral nervous system (PNS). 2. Myelin basic protein (MBP) is a major protein in CNS myelin. 3. MBP is expressed specifically in the nervous system. 4. The MBP gene has been cloned and characterized. 5. Two mutant mice, Shiverer (shi) and myelin-deficient (mld. shimid), are autosomal recessive mutants that show severe symptoms such as intentional tremor. They have been found to have a mutation in the MBP gene that results in poor myelination in the central nervous system. 6. It was found that rearrangement within the MBP gene results in low expression of the gene. 7. In Shiverer, the MBP gene is partially deleted (from exons 3 to 7), and in mld, the gene is duplicated tandemly and a large portion of the duplication is inverted upstream of the intact copy. 8. In mld, anti-sense RNA complementary to exons 3-7, which correspond to the inverted segment, was detected by RNase protection studies, and presumed to be responsible for the reduced expressions of MBP. 9. The mechanism of gene rearrangement in MBP was also characterized. 10. This article reviews the recent progress in the study of the MBP gene, especially the rearrangement of the gene and its expression in mutant mice.

Animals↗