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At least 19 recordsLinked to original sources
PubMed1999

Murine model of autoimmune hearing loss induced by myelin protein P0.

Myelin protein P0 has been identified as an autoantigen in inner ear diseases. In order to study autoimmune hearing loss, we performed brain stem auditory-evoked potential (BAEP) studies on P0-sensitized mice. Two P0-sensitized mice showed hunched posture, poor coat, loss of body weight, and abnormal walking with a waddling gait. About 25% of the P0-sensitized mice developed hearing loss. In the BAEP study, peak latencies of waves I, III, and V and the interpeak latency I-III were prolonged in the P0-sensitized hearing loss group of mice. Hearing thresholds were elevated in this group of mice in comparison with the control mice. Inflammatory cell infiltration was observed in the cochlear nerve region, and a reduced number of spiral ganglion cells was also detected. These results suggest that P0-sensitized mice are a useful model for studying autoimmune inflammation of the peripheral portion of the auditory system.

Animals↗
PubMed2006

Macrophage colony stimulating factor is a crucial factor for the intrinsic macrophage response in mice heterozygously deficient for the myelin protein P0.

Mouse mutants heterozygously deficient for the myelin protein P0 (P0+/-) resemble certain forms of human hereditary neuropathies. Endoneurial macrophages of intrinsic origin are intimately involved in the pathogenesis of the demyelinating neuropathy in these mutants. We have previously shown that deficiency for macrophage colony stimulating factor (M-CSF) prevents an increase of the number of endoneurial macrophages and alleviates the mutants' demyelinating phenotype. The aim of this study was to investigate which population of endoneurial macrophages - long-term resident macrophages or recently infiltrated macrophages - is affected by M-CSF deficiency. For this purpose, we generated bone marrow chimeric mice by transplanting GFP+ bone marrow into P0 mutants (P0+/-) and P0 mutants that lack M-CSF (P0+/- mcsf-op). This enabled us to discriminate recently infiltrated short-term resident GFP+ macrophages from long-term resident GFP- macrophages. Three months after bone marrow transplantation, P0+/- mice expressing M-CSF showed a substantial upregulation and activation of both GFP- and GFP+ macrophages in femoral nerves when compared to P0+/+ mice. In contrast, in P0+/- mcsf-op mutants, both GFP- and GFP+ macrophages did not substantially increase. Only small numbers of GFP+ but no GFP- macrophages were activated and phagocytosed myelin in chimeric P0+/- mcsf-op mutants, possibly reflecting recent activation outside the endoneurium before entering the nerve. Our findings demonstrate that M-CSF is crucial for the activation, in situ increase and myelin phagocytosis of both long-term and short-term resident endoneurial macrophages in P0+/- myelin mutants. M-CSF is, therefore, considered as a target candidate for therapeutic strategies to treat human demyelinating neuropathies.

Animals↗
PubMed2001

No evidence of auditory dysfunction in guinea pigs immunized with myelin P0 protein.

Recent data have focused on the peripheral nerve myelin glycoprotein P0 as a putative autoantigen involved in the autoimmune etiology of some cases of Meniere's disease, idiopathic sensorineural hearing loss and sudden deafness. To determine whether antibodies to myelin P0 can alter cochlear function, 13 healthy guinea pigs were immunized with purified porcine myelin P0 while 10 controls were injected with saline water. The animals were then evaluated for evidence of evolving inner ear disease using immunological, electrophysiological and morphological methods. Twenty-six experimental ears were tested weekly with a brainstem auditory evoked potential technique for a period of 4 months and were compared to 20 control ears. Uniformly, all P0-sensitized guinea pigs showed antibodies to myelin protein P0 as evidenced by ELISA. Clinical signs of inflammatory demyelination were not discernible in P0-sensitized guinea pigs and all the animals were qualitatively normal. No significant increase of evoked potential thresholds was found in the P0-sensitized animals when compared to controls (P>0.05). Peak latencies of waves I, II, III, IV and V and inter-peak latencies in P0-sensitized guinea pigs did not significantly differ from those of controls (P>0.05). Histological sections of inner ear and peripheral nerves were free of disease in both groups. These findings indicate that the sole presence of antibodies to myelin P0 in the sera of guinea pigs or patients suspected of having autoimmune inner ear diseases is unlikely to elicit auditory abnormalities and that additional factors are necessary for the pathogenic development of these disorders.

Animals↗
PubMed2006

Antibody responses to peptides of peripheral nerve myelin proteins P0 and P2 in patients with inflammatory demyelinating neuropathy.

BACKGROUND: Antibodies with reactivity to peripheral nerve myelin have previously been found in the serum, and bound to peripheral nerves of patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). AIM: To investigate the presence of antibodies reactive to specific peptide sequences within the myelin proteins P0 and P2 in patients with GBS, in patients with CIDP, in healthy controls and in patients with other neuropathies (ON). METHODS: Blood was obtained from 48 patients with GBS, 36 with CIDP, 48 with ON and 38 controls. ELISA was used to detect antibody responses to peptides of the human peripheral myelin proteins P0 and P2. Blood samples were collected from patients with GBS in early, peak and recovery stages of GBS to analyse antibody levels throughout the course of the disease. RESULTS: Significantly increased total IgG levels were found in patients with GBS compared with other groups. A higher percentage of patients with GBS at the peak of disease had antibody reactivity to P2(14-25) compared with patients with CIDP and control groups. In patients with GBS and CIDP, the percentages of patients with antibody reactivity to P2(61-70), and peptides derived from P0, were comparable to the control groups. Although some individual patients with GBS had high titres of reactivity to the peptide antigens tested, most patients with GBS and CIDP had levels of antibody similar to controls. CONCLUSION: Our data suggest that increased IgG levels and increased antibody reactivity to P2(14-25) in patients with GBS at the peak of disease may play a contributory role in the disease process in some patients with demyelinating forms of GBS.

Case-Control Studies↗
PubMed1993

Deletion of the serine 34 codon from the major peripheral myelin protein P0 gene in Charcot-Marie-Tooth disease type 1B.

Charcot-Marie-Tooth disease type 1B (CMT1B) is genetically linked to chromosome 1q21-23. The major peripheral myelin protein gene, P0, has been cloned and localized to the same chromosomal region. P0 is a 28 kDa glycoprotein involved in the compaction of the multilamellar myelin sheet and accounts for more than half of the peripheral myelin protein content. We checked whether P0 is altered in CMT1B, and show here that a 3 basepair deletion in exon 2 of the P0 gene is present in all affected individuals of a CMT1B family. The mutation results in the deletion of serine 34 in the extracellular domain of P0, suggesting that alterations of P0 cause CMT1B.

Amino Acid Sequence↗
PubMed2004

Pathology of a mouse mutation in peripheral myelin protein P0 is characteristic of a severe and early onset form of human Charcot-Marie-Tooth type 1B disorder.

Mutations in the gene of the peripheral myelin protein zero (P0) give rise to the peripheral neuropathies Charcot-Marie-Tooth type 1B disease (CMT1B), Déjérine-Sottas syndrome, and congenital hypomyelinating neuropathy. To investigate the pathomechanisms of a specific point mutation in the P0 gene, we generated two independent transgenic mouse lines expressing the pathogenic CMT1B missense mutation Ile106Leu (P0sub) under the control of the P0 promoter on a wild-type background. Both P0sub-transgenic mouse lines showed shivering and ultrastructural abnormalities including retarded myelination, onion bulb formation, and dysmyelination seen as aberrantly folded myelin sheaths and tomacula in all nerve fibers. Functionally, the mutation leads to dispersed compound muscle action potentials and severely reduced conduction velocities. Our observations support the view that the Ile106Leu mutation acts by a dominant-negative gain of function and that the P0sub-transgenic mouse represents an animal model for a severe, tomaculous form of CMT1B.

Action Potentials↗
PubMed1990

High level of expression of the myelin protein P0 in Chinese hamster ovary cells.

The major PNS myelin protein, P0, has been expressed in Chinese hamster ovary cells by transfection with a plasmid containing the P0-cDNA. The expression of P0 at both the RNA and the protein level was greatly increased, without detriment to the cell, by the dihydrofolate reductase-methotrexate strategy of gene amplification. The P0 expressed by these cells was glycosylated (containing approximately equal amounts of the complex and high-mannose type glycoproteins) and reached the plasma membrane. This system is suitable not only for addressing the function of P0 directly, but it also applicable to any protein of which an abundance is needed.

Animals↗
PubMed2006

A dual tyrosine-leucine motif mediates myelin protein P0 targeting in MDCK cells.

Differential targeting of myelin proteins to multiple, biochemically and functionally distinct Schwann cell plasma membrane domains is essential for myelin formation. In this study, we investigated whether the myelin protein P0 contains targeting signals using Madin-Darby canine kidney (MDCK) cells. By confocal microscopy, P0 was localized to MDCK cell basolateral membranes. C-terminal deletion resulted in apical accumulation, and stepwise deletions defined a 15-mer region that was required for basolateral targeting. Alanine substitutions within this region identified the YAML sequence as a functional tyrosine-based targeting signal, with the ML sequence serving as a secondary leucine-based signal. Replacement of the P0 ectodomain with green fluorescent protein altered the distribution of constructs lacking the YAML signal. Coexpression of the myelin-associated glycoprotein did not alter P0 distribution in MDCK cells. The results indicate that P0 contains a hierarchy of targeting signals, which may contribute to P0 localization in myelinating Schwann cells and the pathogenesis in human disease.

Amino Acid Motifs↗
PubMed1990

Recombinant peripheral myelin protein P0 confers both adhesion and neurite outgrowth-promoting properties.

To probe into the functional properties of the major peripheral myelin cell surface glycoprotein P0, its ability to confer adhesion and neurite outgrowth-promoting properties was studied in cell culture. To this aim, P0 was expressed as integral membrane glycoprotein at the surface of CV-1 cells with the help of a recombinant vaccinia virus expression system. Furthermore, the immunoglobulin-like extracellular domain of P0 (P0-ED) was expressed as soluble protein in a bacterial expression system and used as substrate coated to plastic dishes or as competitor in cell adhesion and neurite outgrowth-promoting assays. The adhesion of P0-expressing CV-1 cells to P0-ED substrate was specifically inhibitable by polyclonal P0 antibodies (54% +/- 6%). In addition, the specific interaction between P0 molecules could be reduced (49% +/- 8%) by adding soluble P0-ED to the culture medium, demonstrating that the homophilic interaction between recombinant P0 molecules can be mediated, at least on one partner of interacting molecules, by the unglycosylated Ig-like domain. Substrate-coated P0-ED also conferred adhesion and neurite outgrowth ability to dorsal root ganglion neurons with neurites of a mean length of about 150 microns. This neurite outgrowth was specifically inhibitable by soluble P0 (74% +/- 14%) and P0 antibodies (65% +/- 9%). These observations indicate that P0 is capable of displaying two different types of functional roles in the myelination process of peripheral nerves: The heterophilic interaction with neurons may be responsible for the recognition between axon and myelinating Schwann cell at the onset of myelination, whereas the homophilic interaction may indicate its role in the self-recognition of the apposing loops of Schwann cell surface membranes during the myelination process and in the mature compact myelin sheath.

Animals↗
PubMed2001

Axon damage in CMT due to mutation in myelin protein P0.

We describe a family carrying the Thr148Met mutation in the P0 gene. Contrary to other neuropathies caused by myelin gene defects, no demyeliantion could be found in our biopsies. Based on follow up examinations, extensive morphometry and immunohistochemical analysis we suggest that the mild hypomyelination documented in our family secondarily causes axonal degeneration and axonal loss of large and small fibers which predominates the clinical picture.

Adult↗
PubMed1991

The role of complex carbohydrates in adhesion of the myelin protein, P0.

The most abundant protein of peripheral nerve myelin, a glycoprotein termed P0, is believed to be involved in the compaction of the myelin sheath and is postulated to be the closest relative to the ancestral gene for the immunoglobulin superfamily. Recently, P0 has indeed been shown to behave like a homophilic adhesion molecule via interactions of its extracellular domains. Here we demonstrate the importance of the oligosaccharide moieties of P0 in its functioning as a homophilic adhesion molecule. Expression of the complex form of P0 glycoprotein in transfected Chinese hamster ovary cells greatly increased the adhesiveness of those cells, whereas expression of the high-mannose form of P0 glycoprotein did not. This is the first step in the dissection of P0-P0 interaction at the molecular level.

Animals↗
PubMed1999

The absence of myelin P0 protein produces a novel molecular phenotype in Schwann cells.

In order to better understand the pathogenesis of demyelination in P0 knockout (P0-/-) mice, we analyzed the myelin gene expression and the localization of myelin proteins in P0 null mouse sciatic nerve. We have demonstrated that the severe demyelinating neuropathy of P0-knockout mouse is associated with changes in the program of myelin gene expression. Some changes in myelin gene expression occur early, others occur during adulthood. We also provide evidence that the absence of P0 is associated with changes in the localization of specific paranodal proteins in the peripheral nerve. These data suggest that P0 plays an important role, either directly or indirectly, in the program of Schwann cell gene expression and in the specific distribution of peripheral myelin proteins. Furthermore, myelin gene dysregulation and improper localization of paranodal proteins may account, in part, for the pathogenesis of demyelination in P0-knockout mice, as well as in human demyelinating peripheral neuropathy associated with mutations in the P0 gene.

Animals↗
PubMed1987

P2, P1, and P0 myelin protein expression in developing rat sixth nerve: a quantitative immunocytochemical study.

Myelination and the expression of myelin proteins P2, P1, and P0 were studied quantitatively in the rat sixth cranial nerve during development. The postnatal development and growth of all myelin sheaths in this nerve have been studied morphometrically in a companion paper. Epon-embedded blocks with closely matched topography in the transverse plane were selected from rats perfused at ages 1-4, 8, 15, and 20 days. From each block, serial semithin sections were cut, etched, and immunostained according to the peroxidase-antiperoxidase method with well-characterized polyclonal antisera that reacted specifically with P0 glycoprotein and the basic proteins P1 and P2. The immunoreactivities of individual myelin sheaths were measured by densitometry. Numbers of compact myelin lamellae, myelin spiral lengths, and axon diameters were determined on electronmicrographs of adjacent thin sections. At birth anti-P0 immunoreactivity was found on sheaths with two and more compact lamellae; neither P1 nor P2 immunoreactivity was observed. On day 2, myelin sheaths with five and eight lamellae were stained respectively by anti-P1 and anti-P2. On day 3 the percentages of myelin sheaths stained were substantially higher: P0 95%, P1 78%, P2 15%. By day 4, anti-P0 and anti-P1 immunoreactivity was present in 95% of myelin sheaths; 35% were stained by anti-P2. For P2, staining intensity and percentage of myelin sheaths stained continued to increase and by day 20, 85% were anti-P2-positive. The density of immunoreactivity was not uniform in all myelin sheaths. At young ages staining varied with all three proteins. The variability decreased as myelin sheaths thickened; it persisted longest for anti-P2. We conclude that the density and distribution of immunoreactivities of P0, P1, and P2 reflect their relative concentrations during myelin sheath development and growth. We attribute lack of detectable anti-P2 immunoreactivity in some small sheaths at 20 days to their early stage of myelination and also to limitations of the method. We infer from our observations that all myelin-forming Schwann cells express P2 basic protein.

Abducens Nerve↗
PubMed1993

Homophilic adhesion of the myelin P0 protein requires glycosylation of both molecules in the homophilic pair.

The myelin P0 protein is glycosylated at a single site, asparagine 93, within its only immunoglobulin (Ig)-like domain. We have previously shown that P0 behaves like a homophilic adhesion molecule (Filbin, M. T., F. S. Walsh, B. D. Trapp, J. A. Pizzey, and G. I. Tennekoon. 1990. Nature (Lond.). 344:871-872). To determine if the sugar residues of this molecule contribute to its adhesiveness, the glycosylation site was eliminated by replacing asparagine 93 with an alanine, through site-directed mutagenesis of the P0 cDNA. The mutated P0 cDNA was transfected into CHO cells and surface expression of the mutated P0 was assessed by immunofluorescence, limited trypsinization and an ELISA. A cell line was chosen which expressed approximately equivalent amounts of the unglcosylated P0 (UNGP0) at the cell surface as did a cell line expressing the fully glycosylated P0 (GPo); the adhesive properties of these two cell lines were compared. It was found that when a single cell suspension of the UNGPo cells were incubated, by 60 min, unlike the GP0 cells, they had not formed large aggregates; they were indistinguishable from the control transfected cells. This suggests that the UNGP0 protein does not behave like an adhesion molecule. To establish if only one molecule in the P0:P0 homophilic pair must be glycosylated for adhesion to occur, the ability of UNGP0 cells to adhere to GP0 cells was assessed both qualitatively and quantitatively. The results of both types of assay imply that, indeed, both P0 molecules in the homophilic pair must be glycosylated for adhesion to take place.

Animals↗
PubMed1990

Role of myelin P0 protein as a homophilic adhesion molecule.

Peripheral nervous system myelin is an extension of the Schwann cell's plasma membrane that tightly enwraps axons in many layers and permits nerve impulses to be rapidly conducted. It is not known how these multiple membrane layers are held together in this compact form. Here we present evidence supporting the hypothesis that the extracellular leaflets of myelin are held together by the most abundant protein of myelin of the peripheral nervous system, P0, by homophilic interaction of its extracellular domains. Transfected Chinese hamster ovary cells expressing P0 protein adhere to each other in suspension, to form large aggregates, whereas cells that are identical but which do not express P0 do not. We also show that this aggregation is mediated by homophilic binding between P0-expressing cells and that the apposing plasma membranes of these cells specifically form desmosomes, whereas control transfected cells do not. As the only difference between the two cell populations is the expression of P0, this protein is apparently responsible for the changes in morphology and adhesion in the cells that express it. The idea that P0 is a homophilic adhesion molecule is supported by its inclusion in the immunoglobulin supergene family, all members of which are involved in recognition and/or adhesion.

Animals↗
PubMed1994

Peripheral myelin P0 protein mediates neurite outgrowth of cortical neurons in vitro and axonal regeneration in vivo.

Peripheral myelin P0 protein is a homophilic adhesion molecule of immunoglobulin superfamily to compact myelin structure. In addition to its roles in formation and maintenance of myelin, P0 shows neurite-outgrowth promotion activity of dorsal root ganglions. In this paper, we examined biological activity of P0 in central nervous system (CNS). Neurite outgrowth of cortical neurons of rat embryo was markedly promoted in the co-culture on C6 transformants expressing P0 protein. The neurite outgrowth was not inhibited by the P0-glycopeptide but specifically inhibited by the anti-P0 monoclonal antibody recognizing the extracellular peptide of P0. In in vivo studies, we observed significant axonal regeneration into grafts only in animals implanted with P0-expressing transformants after spinal one-third transection. These results suggest that P0 protein has promoting activity on the neurite elongation in CNS as well as in peripheral nervous system.

Animals↗
PubMed1994

The cytoplasmic domain of the myelin P0 protein influences the adhesive interactions of its extracellular domain.

The extracellular domain of the myelin P0 protein is believed to engage in adhesive interactions and thus hold the myelin membrane compact. We have previously shown that P0 can behave as a homophilic adhesion molecule through interactions of its extracellular domains (Filbin, M. T., F. S. Walsh, B. D. Trapp, J. A. Pizzey, and G. I. Tennekoon. 1990. Nature (Lond.) 344:871-872). To determine if the cytoplasmic domain of P0 must be intact for the extracellular domains to adhere, we compared the adhesive capabilities of P0 proteins truncated at the COOH-terminal to the full-length P0 protein. P0 cDNAs lacking nucleotides coding for the last 52 or 59 amino acids were transfected into CHO cells, and surface expression of the truncated proteins was assessed by immunofluorescence, surface labeling followed by immunoprecipitation, and an ELISA. Cell lines were chosen that expressed at least equivalent amounts of the truncated P0 proteins at the surface as did a cell line expressing the full-length P0. The adhesive properties of these three cell lines were compared. It was found that when a suspension of single cells was allowed to aggregate for a period of 60 min, only the cells expressing the full-length P0 had formed large aggregates, while the cells expressing the truncated P0 molecules were still mostly single cells indistinguishable from the control cells. Furthermore, 25-30% of the full-length P0 was insoluble in NP40, indicative of an interaction with the cytoskeleton, whereas only 5-10% of P0 lacking 52 amino acids and none of P0 lacking 59 amino acids were insoluble. These results suggest that for the extracellular domain of P0 to behave as a homophilic adhesion molecule, its cytoplasmic domain must be intact, and most probably, it is interacting with the cytoskeleton.

Amino Acid Sequence↗
PubMed1996

Cultured Schwann cells constitutively express the myelin protein P0.

It is widely thought that mammalian Schwann cells do not express Po, the major glycoprotein in peripheral myelin, unless they are induced to do so by axonal signals that can be mimicked by agents that trigger cAMP signaling pathways. In contrast, we find that cultured Schwann cells make large amounts of Po without the addition of any axonal-like signal, provided they have not been exposed to serum during the culture process. We also report that glial growth factor/neuregulin inhibits this constitutive Po expression. Myelin basic protein is regulated in a similar way. We suggest that expression of Po by Schwann cells before the onset of myelination may be prevented by inhibitory signals within the nerve, rather than by the absence of a positive signal from axons.

Animals↗