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Vijay K. Kuchroo - One of the best experts on this subject based on the ideXlab platform.
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Prfnted In U.S.A. IDENTIFICATION AND CHARACTERIZATION OF A SECOND ENCEPHALITOGENIC DETERMINANT OF MYELIN Proteolipid Protein (RESIDUES 178-191) FOR SJL MICE'
2015Co-Authors: Judith M. Greer, Vijay K. Kuchroo, Raymond A. Sobel, Marjorie B. LeesctAbstract:We previously described a synthetic peptide of myelin Proteolipid Protein (PLP), peptide 139-151, which induces experimental allergic encephalomye-litis in SJL/J (H-2") mice. We have now identified an additional determinant, PLP residues 178-1 91, that is also a potent encephalitogen in this strain. When PLP peptide 178-191 was compared with peptide 139- 15 1 on an equimolar basis, the day of onset of disease induced by PLP 178-191 was earlier, but the incidence, severity, and histologic features were indistinguishable. Lymph node cells from animals immunized with the whole PLP molecule responded to both PLP 178-191 and 139-151, suggesting im-munologic codominance of the two epitopes. PLP 178-1 91 elicited stronger proliferative response
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myelin Proteolipid Protein specific cd4 cd25 regulatory cells mediate genetic resistance to experimental autoimmune encephalomyelitis
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: N Jayagopala R Reddy, Raymond A. Sobel, Zsolt Illes, Xingmin Zhang, Jeffrey Encinas, Jason Pyrdol, Lindsay B Nicholson, Kai W Wucherpfennig, Vijay K. KuchrooAbstract:SJL mice are highly susceptible to experimental autoimmune encephalomyelitis (EAE) induced with myelin Proteolipid Protein (PLP) peptide 139-151, whereas H-2 congenic B10.S mice are resistant. Immunodominance and susceptibility to EAE are associated with a high precursor frequency of PLP 139-151-specific T cells in the naive repertoire of SJL mice. To understand the mechanism of EAE resistance in B10.S mice, we determined the precursor frequency of PLP 139-151-reactive T cells in both strains by using IAs/PLP 139-151 tetramers. SJL and B10.S mice had similar frequencies of tetramer-reactive T cells in the naive peripheral repertoire. However, in SJL mice, the majority of PLP 139-151 tetramer-positive cells were in the CD4+CD25- population, whereas there were more tetramer-positive cells in the CD4+CD25+ population of B10.S mice. Depletion of CD4+CD25+ cells in vivo facilitated the expansion of PLP 139-151-reactive cells with production of T helper 1 cytokines in EAE-resistant B10.S mice. Furthermore, anti-CD25 Ab treatment before immunization resulted in EAE induction in these otherwise resistant mice. These data indicate an important role for autoantigen-specific CD4+CD25+ cells in genetic resistance to autoimmunity.
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Amelioration of Proteolipid Protein 139-151-induced encephalomyelitis in SJL mice by modified amino acid copolymers and their mechanisms.
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Joel N. H. Stern, Masha Fridkis-hareli, Derin B. Keskin, Zsolt Illes, Jayagopala Reddy, Eric G. Sheu, Hiroyuki Nishimura, Celia F. Brosnan, Laura Santambrogio, Vijay K. KuchrooAbstract:Copolymer 1 [Cop1, glatiramer acetate, Copaxone, poly(Y,E,A,K)n] is widely used in the treatment of relapsing/remitting multiple sclerosis in which it reduces the frequency of relapses by ≈30%. In the present study, copolymers with modified amino acid compositions (based on the binding motif of myelin basic Protein 85–99 to HLA-DR2) have been developed with the aim of suppressing multiple sclerosis more effectively. The enhanced efficacy of these copolymers in experimental autoimmune encephalomyelitis (EAE) induced in SJL/J mice with Proteolipid Protein 139–151 was demonstrated by using three protocols: (i) simultaneous administration of autoantigen and copolymer (termed prevention), (ii) pretreatment with copolymers (vaccination), or (iii) administration of copolymers after disease onset (treatment). Strikingly, in the treatment protocol administration of soluble VWAK and FYAK after onset of disease led to stasis of its progression and suppression of histopathological evidence of EAE. The mechanisms by which these effects are achieved have been examined in several types of assays: binding of copolymers to I-As in competition with Proteolipid Protein 139–151 (blocking), cytokine production by T cells (T helper 2 polarization), and transfer of protection by CD3+ splenocytes or, notably, by copolymer-specific T cell lines (induction of regulatory T cells). The generation of these copolymer-specific regulatory T cells that secrete IL-4 and IL-10 and are independent of the immunizing autoantigen is very prominent among the multiple mechanisms that account for the observed suppressive effect of copolymers in EAE.
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fulminant spontaneous autoimmunity of the central nervous system in mice transgenic for the myelin Proteolipid Protein specific t cell receptor
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Hanspeter Waldner, Raymond A. Sobel, Matthew J Whitters, Mary Collins, Vijay K. KuchrooAbstract:Proteolipid Protein (PLP)-139–151 is the dominant encephalitogenic peptide that induces experimental autoimmune encephalomyelitis (EAE) in SJL (H-2s) mice. To examine the contribution of T cell receptor (TCR) specificity in the induction of EAE, we generated transgenic mice expressing the rearranged TCR genes from an encephalitogenic or a nonencephalitogenic PLP-139–151/I-As-specific T cell clone. Both types of transgenic lines developed spontaneous EAE, but, remarkably, the lines expressing the TCR from the nonencephalitogenic clone showed increasingly higher frequencies of disease (60–83%) in progressive SJL backcrosses and could not be propagated on the susceptible background. The T cells from the transgenic mice were not tolerized, because they responded vigorously to the antigen in vitro and mediated EAE when the mice were immunized with antigen. Besides being the only description of a TCR transgenic mice for the PLP-139–151/I-As epitope, the results demonstrate that the TCR from a nonencephalitogenic PLP-specific T cell clone can induce autoimmune disease when expressed appropriately in vivo.
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immunogenic and encephalitogenic epitope clusters of myelin Proteolipid Protein
Journal of Immunology, 1996Co-Authors: Judith M. Greer, Raymond A. Sobel, Scott Southwood, A Sette, Marjorie B Lees, Vijay K. KuchrooAbstract:To understand and develop strategies to intervene in autoimmune responses to myelin Proteolipid Protein (PLP), encephalitogenic epitopes must be identified. To expedite the identification of potentially immunogenic and encephalitogenic epitopes of PLP, overlapping synthetic 20-mer PLP peptides covering the whole PLP molecule were screened for their ability to bind to purified mouse I-Ad, I-Ak, and I-As molecules. The peptides that bound to the I-A molecules were tested for their ability to induce immune responses in corresponding inbred mouse strains. Immunogenic peptides were then tested for their ability to induce experimental autoimmune encephalomyelitis. Moderate to strong I-A binding was essential for development of immune responses, but immunogenicity was not sufficient for encephalitogenicity. Rather, encephalitogenic epitopes clustered in three regions of the molecule, namely within residues 40-70, 100-119, and 178-209. These were also the regions of the PLP that showed the greatest promiscuity in binding to I-A molecules. Except for PLP 139-151, which is an encephalitogenic determinant in mice expressing I-As, all encephalitogenic epitopes of PLP previously identified, regardless of their MHC class II restriction, are located within or adjacent to these epitope clusters. None of the encephalitogenic epitopes occur in regions of the molecule that have a high degree of homology with the neuronal M6a Protein, a member of the DM20/PLP superfamily. Atypical clinical and histologic patterns of experimental autoimmune encephalomyelitis were observed in some strains of mice sensitized with certain PLP peptides and may reflect induction of T cells with different disease-inducing potentials.
Raymond A. Sobel - One of the best experts on this subject based on the ideXlab platform.
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Prfnted In U.S.A. IDENTIFICATION AND CHARACTERIZATION OF A SECOND ENCEPHALITOGENIC DETERMINANT OF MYELIN Proteolipid Protein (RESIDUES 178-191) FOR SJL MICE'
2015Co-Authors: Judith M. Greer, Vijay K. Kuchroo, Raymond A. Sobel, Marjorie B. LeesctAbstract:We previously described a synthetic peptide of myelin Proteolipid Protein (PLP), peptide 139-151, which induces experimental allergic encephalomye-litis in SJL/J (H-2") mice. We have now identified an additional determinant, PLP residues 178-1 91, that is also a potent encephalitogen in this strain. When PLP peptide 178-191 was compared with peptide 139- 15 1 on an equimolar basis, the day of onset of disease induced by PLP 178-191 was earlier, but the incidence, severity, and histologic features were indistinguishable. Lymph node cells from animals immunized with the whole PLP molecule responded to both PLP 178-191 and 139-151, suggesting im-munologic codominance of the two epitopes. PLP 178-1 91 elicited stronger proliferative response
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myelin Proteolipid Protein specific cd4 cd25 regulatory cells mediate genetic resistance to experimental autoimmune encephalomyelitis
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: N Jayagopala R Reddy, Raymond A. Sobel, Zsolt Illes, Xingmin Zhang, Jeffrey Encinas, Jason Pyrdol, Lindsay B Nicholson, Kai W Wucherpfennig, Vijay K. KuchrooAbstract:SJL mice are highly susceptible to experimental autoimmune encephalomyelitis (EAE) induced with myelin Proteolipid Protein (PLP) peptide 139-151, whereas H-2 congenic B10.S mice are resistant. Immunodominance and susceptibility to EAE are associated with a high precursor frequency of PLP 139-151-specific T cells in the naive repertoire of SJL mice. To understand the mechanism of EAE resistance in B10.S mice, we determined the precursor frequency of PLP 139-151-reactive T cells in both strains by using IAs/PLP 139-151 tetramers. SJL and B10.S mice had similar frequencies of tetramer-reactive T cells in the naive peripheral repertoire. However, in SJL mice, the majority of PLP 139-151 tetramer-positive cells were in the CD4+CD25- population, whereas there were more tetramer-positive cells in the CD4+CD25+ population of B10.S mice. Depletion of CD4+CD25+ cells in vivo facilitated the expansion of PLP 139-151-reactive cells with production of T helper 1 cytokines in EAE-resistant B10.S mice. Furthermore, anti-CD25 Ab treatment before immunization resulted in EAE induction in these otherwise resistant mice. These data indicate an important role for autoantigen-specific CD4+CD25+ cells in genetic resistance to autoimmunity.
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Thiopalmitoylation of myelin Proteolipid Protein epitopes enhances immunogenicity and encephalitogenicity.
Journal of immunology (Baltimore Md. : 1950), 2001Co-Authors: Judith M. Greer, Raymond A. Sobel, Bérangère Denis, Elisabeth TrifilieffAbstract:Proteolipid Protein (PLP) is the most abundant Protein of CNS myelin, and is posttranslationally acylated by covalent attachment of long chain fatty acids to cysteine residues via a thioester linkage. Two of the acylation sites are within epitopes of PLP that are encephalitogenic in SJL/J mice (PLP 104–117 and PLP 139–151 ) and against which increased immune responses have been detected in some multiple sclerosis patients. It is known that attachment of certain types of lipid side chains to peptides can result in their enhanced immunogenicity. The aim of this study was to determine whether thioacylated PLP peptides, as occur in the native Protein, are more immunogenic than their nonacylated counterparts, and whether thioacylation influences the development of autoreactivity and experimental autoimmune encephalomyelitis. The results show that in comparison with nonacylated peptides, thioacylated PLP lipopeptides can induce greater T cell and Ab responses to both the acylated and nonacylated peptides. They also enhanced the development and chronicity of experimental autoimmune encephalomyelitis. Synthetic peptides in which the fatty acid was attached via an amide linkage at the N terminus were not encephalitogenic, and they induced greater proportions of CD8 + cells in initial in vitro stimulation. Therefore, the lability and the site of the linkage between the peptide and fatty acid may be important for induction of encephalitogenic CD4 + T cells. These results suggest that immune responses induced by endogenous thioacylated lipopeptides may contribute to the immunopathogenesis of chronic experimental demyelinating diseases and multiple sclerosis.
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fulminant spontaneous autoimmunity of the central nervous system in mice transgenic for the myelin Proteolipid Protein specific t cell receptor
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Hanspeter Waldner, Raymond A. Sobel, Matthew J Whitters, Mary Collins, Vijay K. KuchrooAbstract:Proteolipid Protein (PLP)-139–151 is the dominant encephalitogenic peptide that induces experimental autoimmune encephalomyelitis (EAE) in SJL (H-2s) mice. To examine the contribution of T cell receptor (TCR) specificity in the induction of EAE, we generated transgenic mice expressing the rearranged TCR genes from an encephalitogenic or a nonencephalitogenic PLP-139–151/I-As-specific T cell clone. Both types of transgenic lines developed spontaneous EAE, but, remarkably, the lines expressing the TCR from the nonencephalitogenic clone showed increasingly higher frequencies of disease (60–83%) in progressive SJL backcrosses and could not be propagated on the susceptible background. The T cells from the transgenic mice were not tolerized, because they responded vigorously to the antigen in vitro and mediated EAE when the mice were immunized with antigen. Besides being the only description of a TCR transgenic mice for the PLP-139–151/I-As epitope, the results demonstrate that the TCR from a nonencephalitogenic PLP-specific T cell clone can induce autoimmune disease when expressed appropriately in vivo.
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immunogenic and encephalitogenic epitope clusters of myelin Proteolipid Protein
Journal of Immunology, 1996Co-Authors: Judith M. Greer, Raymond A. Sobel, Scott Southwood, A Sette, Marjorie B Lees, Vijay K. KuchrooAbstract:To understand and develop strategies to intervene in autoimmune responses to myelin Proteolipid Protein (PLP), encephalitogenic epitopes must be identified. To expedite the identification of potentially immunogenic and encephalitogenic epitopes of PLP, overlapping synthetic 20-mer PLP peptides covering the whole PLP molecule were screened for their ability to bind to purified mouse I-Ad, I-Ak, and I-As molecules. The peptides that bound to the I-A molecules were tested for their ability to induce immune responses in corresponding inbred mouse strains. Immunogenic peptides were then tested for their ability to induce experimental autoimmune encephalomyelitis. Moderate to strong I-A binding was essential for development of immune responses, but immunogenicity was not sufficient for encephalitogenicity. Rather, encephalitogenic epitopes clustered in three regions of the molecule, namely within residues 40-70, 100-119, and 178-209. These were also the regions of the PLP that showed the greatest promiscuity in binding to I-A molecules. Except for PLP 139-151, which is an encephalitogenic determinant in mice expressing I-As, all encephalitogenic epitopes of PLP previously identified, regardless of their MHC class II restriction, are located within or adjacent to these epitope clusters. None of the encephalitogenic epitopes occur in regions of the molecule that have a high degree of homology with the neuronal M6a Protein, a member of the DM20/PLP superfamily. Atypical clinical and histologic patterns of experimental autoimmune encephalomyelitis were observed in some strains of mice sensitized with certain PLP peptides and may reflect induction of T cells with different disease-inducing potentials.
Judith M. Greer - One of the best experts on this subject based on the ideXlab platform.
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Prfnted In U.S.A. IDENTIFICATION AND CHARACTERIZATION OF A SECOND ENCEPHALITOGENIC DETERMINANT OF MYELIN Proteolipid Protein (RESIDUES 178-191) FOR SJL MICE'
2015Co-Authors: Judith M. Greer, Vijay K. Kuchroo, Raymond A. Sobel, Marjorie B. LeesctAbstract:We previously described a synthetic peptide of myelin Proteolipid Protein (PLP), peptide 139-151, which induces experimental allergic encephalomye-litis in SJL/J (H-2") mice. We have now identified an additional determinant, PLP residues 178-1 91, that is also a potent encephalitogen in this strain. When PLP peptide 178-191 was compared with peptide 139- 15 1 on an equimolar basis, the day of onset of disease induced by PLP 178-191 was earlier, but the incidence, severity, and histologic features were indistinguishable. Lymph node cells from animals immunized with the whole PLP molecule responded to both PLP 178-191 and 139-151, suggesting im-munologic codominance of the two epitopes. PLP 178-1 91 elicited stronger proliferative response
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myelin Proteolipid Protein an effective autoantigen and target of autoimmunity in multiple sclerosis
Journal of Autoimmunity, 2008Co-Authors: Judith M. Greer, Michael P PenderAbstract:Myelin Proteolipid Protein (PLP) is the most abundant Protein in central nervous system (CNS) myelin and plays a major role in maintaining the structural and functional integrity of myelin. Its abundance in, and restriction to, CNS myelin and its post-translational modification by acylation make PLP an effective autoantigen, which can induce experimental autoimmune encephalomyelitis in rodents and non-human primates and which is a target of pathogenic autoimmunity in people with multiple sclerosis, a chronic inflammatory demyelinating CNS disease.
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myelin Proteolipid Protein the first 50 years
The International Journal of Biochemistry & Cell Biology, 2002Co-Authors: Judith M. Greer, Marjorie B LeesAbstract:Myelin Proteolipid Protein (PLP), the most abundant Protein of central nervous system (CNS) myelin, is a hydrophobic integral membrane Protein. Because of its physical properties, which make it difficult to work with, progress towards determining the exact function(s) and disease associations of myelin PLP has been slow. However, recent molecular biology advances have given new life to investigations of PLP, and suggest that it has multiple functions within myelin and is of importance in several neurological disorders.
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Thiopalmitoylation of myelin Proteolipid Protein epitopes enhances immunogenicity and encephalitogenicity.
Journal of immunology (Baltimore Md. : 1950), 2001Co-Authors: Judith M. Greer, Raymond A. Sobel, Bérangère Denis, Elisabeth TrifilieffAbstract:Proteolipid Protein (PLP) is the most abundant Protein of CNS myelin, and is posttranslationally acylated by covalent attachment of long chain fatty acids to cysteine residues via a thioester linkage. Two of the acylation sites are within epitopes of PLP that are encephalitogenic in SJL/J mice (PLP 104–117 and PLP 139–151 ) and against which increased immune responses have been detected in some multiple sclerosis patients. It is known that attachment of certain types of lipid side chains to peptides can result in their enhanced immunogenicity. The aim of this study was to determine whether thioacylated PLP peptides, as occur in the native Protein, are more immunogenic than their nonacylated counterparts, and whether thioacylation influences the development of autoreactivity and experimental autoimmune encephalomyelitis. The results show that in comparison with nonacylated peptides, thioacylated PLP lipopeptides can induce greater T cell and Ab responses to both the acylated and nonacylated peptides. They also enhanced the development and chronicity of experimental autoimmune encephalomyelitis. Synthetic peptides in which the fatty acid was attached via an amide linkage at the N terminus were not encephalitogenic, and they induced greater proportions of CD8 + cells in initial in vitro stimulation. Therefore, the lability and the site of the linkage between the peptide and fatty acid may be important for induction of encephalitogenic CD4 + T cells. These results suggest that immune responses induced by endogenous thioacylated lipopeptides may contribute to the immunopathogenesis of chronic experimental demyelinating diseases and multiple sclerosis.
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surges of increased t cell reactivity to an encephalitogenic region of myelin Proteolipid Protein occur more often in patients with multiple sclerosis than in healthy subjects
Journal of Immunology, 2000Co-Authors: Michael P Pender, Judith M. Greer, Peter A Csurhes, Paul D Mowat, Robert D Henderson, K D Cameron, David M Purdie, Pamela A Mccombe, Michael F GoodAbstract:We have previously shown that patients with multiple sclerosis (MS) have increased T cell responses to the immunodominantregion (residues 184–209) of myelin Proteolipid Protein (PLP). The present study investigated whether this reactivity fluctuatesover time and correlates with disease activity. We performed monthly limiting dilution assays for 12–16 mo in four healthysubjects and five patients with relapsing-remitting MS to quantify the frequencies of circulating T cells proliferating in responseto PLP
James Garbern - One of the best experts on this subject based on the ideXlab platform.
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diffusion tensor imaging of patients with Proteolipid Protein 1 gene mutations
Journal of Neuroscience Research, 2014Co-Authors: Jeremy J Laukka, Tori Lafleur, Jeffrey A Stanley, Malek I Makki, John Kamholz, James GarbernAbstract:Pelizaeus-Merzbacher disease (PMD) is an X-linked disorder of the central nervous system (CNS) caused by a wide variety of mutations affecting Proteolipid Protein 1 (PLP1). We assessed the effects of PLP1 mutations on water diffusion in CNS white matter by using diffusion tensor imaging. Twelve patients with different PLP1 point mutations encompassing a range of clinical phenotypes were analyzed, and the results were compared with a group of 12 age-matched controls. The parallel (λ// ), perpendicular (λ⊥ ), and apparent diffusion coefficients (ADC) and fractional anisotropy were measured in both limbs of the internal capsule, the genu and splenium of corpus callosum, the base of the pons, and the cerebral peduncles. The mean ADC and λ⊥ in the PMD patient group were both significantly increased in all selected structures, except for the base of the pons, compared with controls. PMD patients with the most severe disease, however, had a significant increase of both λ// and λ⊥ . In contrast, more mildly affected patients had much smaller changes in λ// and λ⊥ . These data suggest that myelin, the structure responsible in part for the λ⊥ barrier, is the major site of disease pathogenesis in this heterogeneous group of patients. Axons, in contrast, the structures mainly responsible for λ// , are much less affected, except within the subgroup of patients with the most severe disease. Clinical disability in patients with PLP1 point mutation is thus likely determined by the extent of pathological involvement of both myelin and axons, with alterations of both structures causing the most severe disease. © 2014 Wiley Periodicals, Inc.
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steroid responsive neurologic relapses in a child with a Proteolipid Protein 1 mutation
Neurology, 2007Co-Authors: Mark P Gorman, L E Walsh, Grace M Hobson, R. Phillip Kinkel, Basil T. Darras, James Garbern, David K. Urion, Meredith R. Golomb, Yaman Z EksiogluAbstract:A 10-year-old boy developed corticosteroid-responsive relapsing neurologic signs, including nystagmus and ataxia. MRI revealed multifocal T2 white matter hyperintensities; several were gadolinium-enhancing. CSF contained oligoclonal bands. Although the patient met criteria for multiple sclerosis (MS), the Proteolipid Protein-1 gene (PLP1) contained a mutation in exon 3B (c.409C>T), predicting a tryptophan-for-arginine substitution. This case raises questions about the role of inflammation in PLP1-related disorders and, conversely, PLP1 mutations in MS.
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peripheral neuropathy caused by Proteolipid Protein gene mutations
Annals of the New York Academy of Sciences, 1999Co-Authors: James Garbern, Anders A F Sima, Franca Cambi, Jean Michel Vallat, Richard A Lewis, Michael E Shy, George H Kraft, M E Hodes, E P Bosch, Stephen R. DlouhyAbstract:Pelizaeus-Merzbacher disease (PMD) is a dysmyelinating disorder of the central nervous system typically caused by duplications or missense mutations of the Proteolipid Protein (PLP) gene. Most investigators have found that peripheral nerve function and structure is normal in PMD patients. We have found that null mutations of the PLP gene cause demyelinating peripheral neuropathy, whereas duplications and a proline 14 to leucine mutation do not affect nerve function. A family with a nonsense mutation at position 144, which affects only PLP but not the alternatively spliced gene product DM20, has a very mild syndrome, including normal peripheral nerve function. Our findings suggest that DM20 alone is sufficient to maintain normal nerve function and that there may be domains of PLP/DM20 that have a relatively more active role in the peripheral nervous system compared with that in the central nervous system.
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Proteolipid Protein is necessary in peripheral as well as central myelin
Neuron, 1997Co-Authors: James Garbern, Anders A F Sima, Franca Cambi, Xue Ming Tang, Jean Michel Vallat, Peter E Bosch, Richard A Lewis, Michael E Shy, Jasloveleen Sohi, George H KraftAbstract:Alternative products of the Proteolipid Protein gene (PLP), Proteolipid Protein (PLP) and DM20, are major components of compact myelin in the central nervous system, but quantitatively minor constituents of Schwann cells. A family with a null allele of PLP has a less severe CNS phenotype than those with other types of PLP mutations. Moreover, individuals with PLP null mutations have a demyelinating peripheral neuropathy, not seen with other PLP mutations of humans or animals. Direct analysis of normal peripheral nerve demonstrates that PLP is localized to compact myelin. This and the clinical and pathologic observations of the PLP null phenotype indicate that PLP/DM20 is necessary for proper myelin function both in the central and peripheral nervous systems.
Catherine Vaursbarriere - One of the best experts on this subject based on the ideXlab platform.
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novel neuronal Proteolipid Protein isoforms encoded by the human myelin Proteolipid Protein 1 gene
Neuroscience, 2010Co-Authors: Catherine Sarret, Patricia Combes, Odile Boespflugtanguy, Philippe Micheau, A. Gelot, Catherine VaursbarriereAbstract:The human myelin Proteolipid Protein 1 gene (hPLP1), which encodes the major structural myelin Proteins of the central nervous system (CNS), is classically described as expressed in the oligodendrocytes, the CNS myelinating cells. We identified two new exons in the intron 1 of the hPLP1 gene that lead to the expression of additional mRNA and Protein isoforms mainly expressed in neurons instead of oligodendrocytes. Those novel neuronal PLP isoforms are detected as soon as human fetal development and their concomitant expression is specific of the human species. As classical PLP Proteins, the novel Protein isoforms seem to be addressed to the plasma membrane. These results suggest for the first time that PLP may have functions in humans not only in oligodendrocytes but also in neurons and could be implicated in axono-glial communication. Moreover, this neuronal expression of the hPLP1 gene might explain the neuronal dysfunctions in patients carrying hPLP1 gene mutations.
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insertion of mutant Proteolipid Protein results in missorting of myelin Proteins
Annals of Neurology, 2003Co-Authors: Catherine Vaursbarriere, Kondi Wong, Thais Weibel, Mones Abuasab, Michael Weiss, Christine R Kaneski, Tong Hui Mixon, S Bonavita, Isabelle Creveaux, John D HeissAbstract:The PLP gene maps to the long arm of the human X chromosome at Xq21–q22 and encodes for the two major myelin Proteins of the central nervous system (CNS), the Proteolipid Protein (PLP), and its spliced isoform DM20.1 PLP is the major structural component of CNS myelin, whereas DM20, which is produced earlier in CNS development, may be involved in oligodendrocyte differentiation and survival,2 as well as in the maintenance of myelin compaction.3 Additional alternative splicing products with a soma-restricted expression (sr-PLP and sr-DM20) has been found in mice. In addition to oligodendrocytes, these sr-PLP/DM20 Proteins also are expressed by several classes of neurons.4 In humans, the clinical findings associated with PLP mutations are spread over a wide continuum, extending from the most severe form of Pelizaeus–Merzbacher disease to the relatively mild, late-onset spastic paraplegia, leading to the concept of PLP-related disorders.5–7 A demyelinating peripheral neuropathy is frequently observed in PLP1 null mutations8 and mutations which truncate PLP1 expression within the PLP1-specific domain without alteration of DM20 expression.9 In our investigation of patients with leukodystrophies of unknown cause, we identified a novel PLP mutation associated with aggregation and abnormal distribution of myelin Proteins in the peripheral nervous system (PNS).
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insertion of mutant Proteolipid Protein results in missorting of myelin Proteins
Annals of Neurology, 2003Co-Authors: Catherine Vaursbarriere, Kondi Wong, Thais Weibel, Mones Abuasab, Christine R Kaneski, Tong Hui Mixon, S Bonavita, Isabelle Creveaux, Michael D Weiss, John D HeissAbstract:Two brothers with a leukodystrophy, progressive spastic diplegia, and peripheral neuropathy were found to have Proteinaceous aggregates in the peripheral nerve myelin sheath. The patients' mother had only subclinical peripheral neuropathy, but the maternal grandmother had adult-onset leukodystrophy. Sequencing of the Proteolipid Protein (PLP) gene showed a point mutation IVS4 + 1 G-->A within the donor splice site of intron 4. We identified one transcript with a deletion of exon 4 (Deltaex4, 169bp) encoding for PLP and DM20 Proteins and lacking two transmembrane domains, and a second transcript with exon 4 + 10bp encoding three transmembrane domains. Immunohistochemistry showed abnormal aggregation in the myelin sheath of MBP and P0. Myelin-associated glycoProtein was present in the Schmidt-Lanterman clefts but significantly reduced in the periaxonal region. Using immunogold electron microscopy, we demonstrated the presence of mutated PLP/DM20 and the absence of the intact Protein in the patient peripheral myelin sheath. We conclude that insertion of mutant PLP/DM20 with resulting aberrant distribution of other myelin Proteins in peripheral nerve may constitute an important mechanism of dysmyelination in disorders associated with PLP mutations.
