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Eric M. Shooter - One of the best experts on this subject based on the ideXlab platform.
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aggresome formation in neuropathy models based on peripheral Myelin Protein 22 mutations
Journal of The Peripheral Nervous System, 2002Co-Authors: Mary C Ryan, Eric M. Shooter, Lucia NotterpekAbstract:Alterations in peripheral Myelin Protein 22 (PMP22) gene expression are associated with deMyelinating peripheral neuropathies. Overexpression of wild type (wt) PMP22 or inhibition of proteasomal degradation lead to the formation of aggresomes, intracellular ubiquitinated PMP22 aggregates. Aggresome formation has now been observed with two mutant PMP22s, the Tr- and TrJ-PMP22 when the proteasome is inhibited. The formation of these aggresomes required intact microtubules and involved the recruitment of chaperones, including Hsp40, Hsp70, and alphaB-crystallin. Spontaneously formed ubiquitinated PMP22 aggregates were also observed in Schwann cells of homozygous TrJ mice. Significant upregulation of both the ubiquitin-proteasomal and lysosomal pathways occurred in affected nerves suggesting that two pathways of PMP22 degradation are present. Thus, the presence of aggresomes appears to be a common finding in neuropathy models of PMP22 overexpression and of some point mutations known to cause neuropathy in mice and humans.
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Neurons Promote the Translocation of Peripheral Myelin Protein 22 into Myelin
The Journal of Neuroscience, 1997Co-Authors: Sangeeta Pareek, Lucia Notterpek, G. J. Snipes, Roland Naef, Wayne S. Sossin, Laliberté J, Iacampo S, Ueli Suter, Eric M. Shooter, Richard A. MurphyAbstract:Schwann cells express low levels of Myelin Proteins in the absence of neurons. When Schwann cells and neurons are cultured together the production of Myelin Proteins is elevated, and Myelin is formed. For peripheral Myelin Protein 22 (PMP22), the exact amount of Protein produced is critical, because peripheral neuropathies result from its underexpression or overexpression. In this study we examined the effect of neurons on Schwann cell PMP22 production in culture and in peripheral nerve using metabolic labeling and pulse-chase studies as well as immunocytochemistry. Most of the newly synthesized PMP22 in Schwann cells is rapidly degraded in the endoplasmic reticulum. Only a small proportion of the total PMP22 acquires complex glycosylation and accumulates in the Golgi compartment. This material is translocated to the Schwann cell membrane in detectable amounts only when axonal contact and Myelination occur. Myelination does not, however, alter the rapid turnover of PMP22 in Schwann cells. PMP22 may therefore be a unique Myelin Protein in that axonal contact promotes its insertion into the Schwann cell membrane and Myelin without altering its rapid turnover rate within the cell.
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a leucine to proline mutation in the putative first transmembrane domain of the 22 kda peripheral Myelin Protein in the trembler j mouse
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Ueli Suter, G. J. Snipes, A A Welcher, J J Moskow, B Kosaras, Richard L Sidman, A M Buchberg, Eric M. ShooterAbstract:Peripheral Myelin Protein PMP-22 is a potential growth-regulating Myelin Protein that is expressed by Schwann cells and predominantly localized in compact peripheral Myelin. A point mutation in the Pmp-22 gene of inbred trembler (Tr) mice was identified and proposed to be responsible for the Tr phenotype, which is characterized by paralysis of the limbs as well as tremors and transient seizures. In support of this hypothesis, we now report the fine mapping of the Pmp-22 gene to the immediate vicinity of the Tr locus on mouse chromosome 11. Furthermore, we have found a second point mutation in the Pmp-22 gene of trembler-J (TrJ) mice, which results in the substitution of a leucine residue by a proline residue in the putative first transmembrane region of the PMP-22 polypeptide. Tr and TrJ were previously mapped genetically as possible allelic mutations giving rise to similar, but not identical, phenotypes. This finding is consistent with the discovery of two different mutations in physicochemically similar domains of the PMP-22 Protein. Our results strengthen the hypothesis that mutations in the Pmp-22 gene can lead to heterogeneous forms of peripheral neuropathies and offer clues toward possible explanations for the dominant inheritance of these disorders.
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characterization of a novel peripheral nervous system Myelin Protein pmp 22 sr13
Journal of Cell Biology, 1992Co-Authors: G. J. Snipes, Ueli Suter, A A Welcher, Eric M. ShooterAbstract:We have recently described a novel cDNA, SR13 (Welcher, A. A., U. Suter, M. De Leon, G. J. Snipes, and E. M. Shooter. 1991. Proc. Natl. Acad. Sci. USA. 88:7195-7199), that is repressed after sciatic nerve crush injury and shows homology to both the growth arrest-specific mRNA, gas3 (Manfioletti, G., M. E. Ruaro, G. Del Sal, L. Philipson, and C. Schneider, 1990. Mol. Cell Biol. 10:2924-2930), and to the Myelin Protein, PASII (Kitamura, K., M. Suzuki, and K. Uyemura. 1976. Biochim. Biophys. Acta. 455:806-816). In this report, we show that the 22-kD SR13 Protein is expressed in the compact portion of essentially all Myelinated fibers in the peripheral nervous system. Although SR13 mRNA was found in the central nervous system, no corresponding SR13 Protein could be detected by either immunoblot analysis or by immunohistochemistry. Northern and immunoblot analysis of SR13 mRNA and Protein expression during development of the peripheral nervous system reveal a pattern similar to other Myelin Proteins. Furthermore, we demonstrate by in situ mRNA hybridization on tissue sections and on individual nerve fibers that SR13 mRNA is produced predominantly by Schwann cells. We conclude that the SR13 Protein is apparently exclusively expressed in the peripheral nervous system where it is a major component of Myelin. Thus, we propose the name Peripheral Myelin Protein-22 (PMP-22) for the Proteins and cDNA previously designated PASII, SR13, and gas3.
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Characterization of a novel peripheral nervous system Myelin Protein (PMP-22/SR13)
Journal of Cell Biology, 1992Co-Authors: G. J. Snipes, Ueli Suter, A A Welcher, Eric M. ShooterAbstract:We have recently described a novel cDNA, SR13 (Welcher, A. A., U. Suter, M. De Leon, G. J. Snipes, and E. M. Shooter. 1991. Proc. Natl. Acad. Sci. USA. 88:7195-7199), that is repressed after sciatic nerve crush injury and shows homology to both the growth arrest-specific mRNA, gas3 (Manfioletti, G., M. E. Ruaro, G. Del Sal, L. Philipson, and C. Schneider, 1990. Mol. Cell Biol. 10:2924-2930), and to the Myelin Protein, PASII (Kitamura, K., M. Suzuki, and K. Uyemura. 1976. Biochim. Biophys. Acta. 455:806-816). In this report, we show that the 22-kD SR13 Protein is expressed in the compact portion of essentially all Myelinated fibers in the peripheral nervous system. Although SR13 mRNA was found in the central nervous system, no corresponding SR13 Protein could be detected by either immunoblot analysis or by immunohistochemistry. Northern and immunoblot analysis of SR13 mRNA and Protein expression during development of the peripheral nervous system reveal a pattern similar to other Myelin Proteins. Furthermore, we demonstrate by in situ mRNA hybridization on tissue sections and on individual nerve fibers that SR13 mRNA is produced predominantly by Schwann cells. We conclude that the SR13 Protein is apparently exclusively expressed in the peripheral nervous system where it is a major component of Myelin. Thus, we propose the name Peripheral Myelin Protein-22 (PMP-22) for the Proteins and cDNA previously designated PASII, SR13, and gas3.
G. J. Snipes - One of the best experts on this subject based on the ideXlab platform.
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Neurons Promote the Translocation of Peripheral Myelin Protein 22 into Myelin
The Journal of Neuroscience, 1997Co-Authors: Sangeeta Pareek, Lucia Notterpek, G. J. Snipes, Roland Naef, Wayne S. Sossin, Laliberté J, Iacampo S, Ueli Suter, Eric M. Shooter, Richard A. MurphyAbstract:Schwann cells express low levels of Myelin Proteins in the absence of neurons. When Schwann cells and neurons are cultured together the production of Myelin Proteins is elevated, and Myelin is formed. For peripheral Myelin Protein 22 (PMP22), the exact amount of Protein produced is critical, because peripheral neuropathies result from its underexpression or overexpression. In this study we examined the effect of neurons on Schwann cell PMP22 production in culture and in peripheral nerve using metabolic labeling and pulse-chase studies as well as immunocytochemistry. Most of the newly synthesized PMP22 in Schwann cells is rapidly degraded in the endoplasmic reticulum. Only a small proportion of the total PMP22 acquires complex glycosylation and accumulates in the Golgi compartment. This material is translocated to the Schwann cell membrane in detectable amounts only when axonal contact and Myelination occur. Myelination does not, however, alter the rapid turnover of PMP22 in Schwann cells. PMP22 may therefore be a unique Myelin Protein in that axonal contact promotes its insertion into the Schwann cell membrane and Myelin without altering its rapid turnover rate within the cell.
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Peripheral Myelin Protein 22: facts and hypotheses.
Journal of Neuroscience Research, 1995Co-Authors: Ueli Suter, G. J. SnipesAbstract:Mutations affecting the peripheral Myelin Protein 22 (PMP22) gene are associated with inherited motor and sensory neuropathies in mouse (Trembler and Trembler-J) and human (Charcot-Marie-Tooth disease type 1A and Dejerine-Sottas syndrome). Although genetic studies have established a critical role of PMP22 in the formation and/or maintenance of Myelin in the peripheral nervous system, the biological function of PMP22 in Myelin and in non-Myelin forming cells remains largely enigmatic. In this Mini-Review, we will summarize the current knowledge about PMP22 and discuss its hypothetical function(s) in a broad context.
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a leucine to proline mutation in the putative first transmembrane domain of the 22 kda peripheral Myelin Protein in the trembler j mouse
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Ueli Suter, G. J. Snipes, A A Welcher, J J Moskow, B Kosaras, Richard L Sidman, A M Buchberg, Eric M. ShooterAbstract:Peripheral Myelin Protein PMP-22 is a potential growth-regulating Myelin Protein that is expressed by Schwann cells and predominantly localized in compact peripheral Myelin. A point mutation in the Pmp-22 gene of inbred trembler (Tr) mice was identified and proposed to be responsible for the Tr phenotype, which is characterized by paralysis of the limbs as well as tremors and transient seizures. In support of this hypothesis, we now report the fine mapping of the Pmp-22 gene to the immediate vicinity of the Tr locus on mouse chromosome 11. Furthermore, we have found a second point mutation in the Pmp-22 gene of trembler-J (TrJ) mice, which results in the substitution of a leucine residue by a proline residue in the putative first transmembrane region of the PMP-22 polypeptide. Tr and TrJ were previously mapped genetically as possible allelic mutations giving rise to similar, but not identical, phenotypes. This finding is consistent with the discovery of two different mutations in physicochemically similar domains of the PMP-22 Protein. Our results strengthen the hypothesis that mutations in the Pmp-22 gene can lead to heterogeneous forms of peripheral neuropathies and offer clues toward possible explanations for the dominant inheritance of these disorders.
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characterization of a novel peripheral nervous system Myelin Protein pmp 22 sr13
Journal of Cell Biology, 1992Co-Authors: G. J. Snipes, Ueli Suter, A A Welcher, Eric M. ShooterAbstract:We have recently described a novel cDNA, SR13 (Welcher, A. A., U. Suter, M. De Leon, G. J. Snipes, and E. M. Shooter. 1991. Proc. Natl. Acad. Sci. USA. 88:7195-7199), that is repressed after sciatic nerve crush injury and shows homology to both the growth arrest-specific mRNA, gas3 (Manfioletti, G., M. E. Ruaro, G. Del Sal, L. Philipson, and C. Schneider, 1990. Mol. Cell Biol. 10:2924-2930), and to the Myelin Protein, PASII (Kitamura, K., M. Suzuki, and K. Uyemura. 1976. Biochim. Biophys. Acta. 455:806-816). In this report, we show that the 22-kD SR13 Protein is expressed in the compact portion of essentially all Myelinated fibers in the peripheral nervous system. Although SR13 mRNA was found in the central nervous system, no corresponding SR13 Protein could be detected by either immunoblot analysis or by immunohistochemistry. Northern and immunoblot analysis of SR13 mRNA and Protein expression during development of the peripheral nervous system reveal a pattern similar to other Myelin Proteins. Furthermore, we demonstrate by in situ mRNA hybridization on tissue sections and on individual nerve fibers that SR13 mRNA is produced predominantly by Schwann cells. We conclude that the SR13 Protein is apparently exclusively expressed in the peripheral nervous system where it is a major component of Myelin. Thus, we propose the name Peripheral Myelin Protein-22 (PMP-22) for the Proteins and cDNA previously designated PASII, SR13, and gas3.
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Characterization of a novel peripheral nervous system Myelin Protein (PMP-22/SR13)
Journal of Cell Biology, 1992Co-Authors: G. J. Snipes, Ueli Suter, A A Welcher, Eric M. ShooterAbstract:We have recently described a novel cDNA, SR13 (Welcher, A. A., U. Suter, M. De Leon, G. J. Snipes, and E. M. Shooter. 1991. Proc. Natl. Acad. Sci. USA. 88:7195-7199), that is repressed after sciatic nerve crush injury and shows homology to both the growth arrest-specific mRNA, gas3 (Manfioletti, G., M. E. Ruaro, G. Del Sal, L. Philipson, and C. Schneider, 1990. Mol. Cell Biol. 10:2924-2930), and to the Myelin Protein, PASII (Kitamura, K., M. Suzuki, and K. Uyemura. 1976. Biochim. Biophys. Acta. 455:806-816). In this report, we show that the 22-kD SR13 Protein is expressed in the compact portion of essentially all Myelinated fibers in the peripheral nervous system. Although SR13 mRNA was found in the central nervous system, no corresponding SR13 Protein could be detected by either immunoblot analysis or by immunohistochemistry. Northern and immunoblot analysis of SR13 mRNA and Protein expression during development of the peripheral nervous system reveal a pattern similar to other Myelin Proteins. Furthermore, we demonstrate by in situ mRNA hybridization on tissue sections and on individual nerve fibers that SR13 mRNA is produced predominantly by Schwann cells. We conclude that the SR13 Protein is apparently exclusively expressed in the peripheral nervous system where it is a major component of Myelin. Thus, we propose the name Peripheral Myelin Protein-22 (PMP-22) for the Proteins and cDNA previously designated PASII, SR13, and gas3.
Charles R. Sanders - One of the best experts on this subject based on the ideXlab platform.
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peripheral Myelin Protein 22 preferentially partitions into ordered phase membrane domains
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Justin T Marinko, Charles R. Sanders, Anne K KenworthyAbstract:The ordered environment of cholesterol-rich membrane nanodomains is thought to exclude many transmembrane (TM) Proteins. Nevertheless, some multispan helical transmembrane Proteins have been proposed to partition into these environments. Here, giant plasma membrane vesicles (GPMVs) were employed to quantitatively show that the helical tetraspan peripheral Myelin Protein 22 (PMP22) exhibits a pronounced preference for, promotes the formation of, and stabilizes ordered membrane domains. Neither S-palmitoylation of PMP22 nor its putative cholesterol binding motifs are required for this preference. In contrast, Charcot-Marie-Tooth disease-causing mutations that disrupt the stability of PMP22 tertiary structure reduce or eliminate this preference in favor of the disordered phase. These studies demonstrate that the ordered phase preference of PMP22 derives from global structural features associated with the folded form of this Protein, providing a glimpse at the structural factors that promote raft partitioning for multispan helical membrane Proteins.
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peripheral Myelin Protein 22 preferentially partitions into ordered phase membrane domains
bioRxiv, 2020Co-Authors: Justin T Marinko, Anne K Kenworthy, Charles R. SandersAbstract:The ordered environment of membrane rafts is thought to exclude many transmembrane Proteins. Nevertheless, some multi-pass transmembrane Proteins have been proposed to partition into ordered domains. Here, giant plasma membrane vesicles (GPMVs) were employed to quantitatively show that the tetraspan peripheral Myelin Protein 22 (PMP22) exhibits a pronounced preference for, promotes the formation of, and stabilizes ordered membrane domains. Neither S-palmitoylation of PMP22 nor its putative cholesterol binding motifs are required for partitioning to ordered domains. In contrast, disruption of its unusual first transmembrane helix (TM1) reduced ordered phase preference. Charcot-Marie-Tooth disease-causing mutations that destabilize PMP22 also reduced or eliminated this preference in favor of the disordered phase. These studies demonstrate PMP22s ordered phase preference derives both from the distinctive properties of TM1 and global structural features associated with its transmembrane domain, providing a first glimpse at the structural factors that promote raft partitioning for multi-pass Proteins. Significance StatementThe preferential partitioning of single span membrane Proteins for the ordered phase of ordered/disordered phase-separated membranes is now reasonably well understood, but little is known about this phase preferences of multi-pass membrane Proteins. Here, it is shown that the disease-linked tetraspan integral membrane Protein, PMP22, displays a pronounced preference to partition into the ordered phase, a preference that is reversed by disease mutations. This phase preference may be related to the role of PMP22 in cholesterol homeostasis in Myelinating Schwann cells, a role that is also known to be disrupted under conditions of CMTD peripheral neuropathy caused by pmp22 mutations.
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peripheral Myelin Protein 22 modulates store operated calcium channel activity providing insights into charcot marie tooth disease etiology
Journal of Biological Chemistry, 2019Co-Authors: Carlos G Vanoye, Malathi Narayan, Charles R. Sanders, Masayoshi Sakakura, Rose M Follis, Alexandra J Trevisan, Bruce D. CarterAbstract:Charcot-Marie-Tooth (CMT) disease is a peripheral neuropathy associated with gene duplication and point mutations in the peripheral Myelin Protein 22 (PMP22) gene. However, the role of PMP22 in Schwann cell physiology and the mechanisms by which PMP22 mutations cause CMT are not well-understood. On the basis of homology between PMP22 and Proteins associated with modulation of ion channels, we hypothesized that PMP22 alters ion channel activity. Using whole-cell electrophysiology, we show here that heterologous PMP22 expression increases the amplitude of currents similar to those ascribed to store-operated calcium (SOC) channels, particularly those involving transient receptor canonical channel 1 (TrpC1). These channels help replenish Ca2+ in the endoplasmic reticulum (ER) following stimulus-induced depletion. Currents with similar properties were recorded in WT but not pmp22 -/- mouse Schwann cells. Heterologous expression of the CMT-associated PMP22_L16P variant, which fails to reach the plasma membrane and localizes to the ER, led to larger currents than WT PMP22. Similarly, Schwann cells isolated from Trembler J (TrJ; PMP22_L16P) mice had larger currents than WT littermates. Calcium imaging in live nerves and cultured Schwann cells revealed elevated intracellular Ca2+ in TrJ mice compared with WT. Moreover, we found that PMP22 co-immunoprecipitated with stromal interaction molecule 1 (STIM1), the Ca2+ sensor SOC channel subunit in the ER. These results suggest that in the ER, PMP22 interacts with STIM1 and increases Ca2+ influx through SOC channels. Excess or mutant PMP22 in the ER may elevate intracellular Ca2+ levels, which could contribute to CMT pathology.
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Reversible Folding of Human Peripheral Myelin Protein 22, a Tetraspan Membrane Protein
Biochemistry, 2013Co-Authors: Jonathan P. Schlebach, Dungeng Peng, Brett M. Kroncke, Kathleen F. Mittendorf, Malathi Narayan, Bruce D. Carter, Charles R. SandersAbstract:Misfolding of the α-helical membrane Protein peripheral Myelin Protein 22 (PMP22) has been implicated in the pathogenesis of the common neurodegenerative disease known as Charcot-Marie-Tooth diseas...
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mutations of peripheral Myelin Protein 22 result in defective trafficking through mechanisms which may be common to diseases involving tetraspan membrane Proteins
Biochemistry, 2001Co-Authors: Charles R. Sanders, Faramarz Ismailbeigi, Maureen W MceneryAbstract:Phenotypes of several heritable disorders including forms of hearing loss, Myelin diseases, hypomagnesemia, and cataracts are linked to missense mutations in single alleles encoding membrane Proteins having four transmembrane spans. In some cases, the mutant Proteins exhibit dominant negative or gain-of-function behavior whereby heterozygous coexpression of mutant and wild-type genes leads to more serious pathology than is the case for individuals in which only a single wild-type allele is expressed. An example is found in the relationship of peripheral Myelin Protein 22 (PMP22) to Charcot−Marie−Tooth disease (CMTD) type 1A. A number of disease-linked PMP22 mutants fail to undergo normal trafficking beyond the endoplasmic reticulum or intermediate compartment to reach the cell surface. Moreover, recent evidence suggests that pathology resulting from this mistrafficking-based loss of function may also be augmented by the ability of some mutants to disrupt normal trafficking of the product of the wild-type ...
Ueli Suter - One of the best experts on this subject based on the ideXlab platform.
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Neurons Promote the Translocation of Peripheral Myelin Protein 22 into Myelin
The Journal of Neuroscience, 1997Co-Authors: Sangeeta Pareek, Lucia Notterpek, G. J. Snipes, Roland Naef, Wayne S. Sossin, Laliberté J, Iacampo S, Ueli Suter, Eric M. Shooter, Richard A. MurphyAbstract:Schwann cells express low levels of Myelin Proteins in the absence of neurons. When Schwann cells and neurons are cultured together the production of Myelin Proteins is elevated, and Myelin is formed. For peripheral Myelin Protein 22 (PMP22), the exact amount of Protein produced is critical, because peripheral neuropathies result from its underexpression or overexpression. In this study we examined the effect of neurons on Schwann cell PMP22 production in culture and in peripheral nerve using metabolic labeling and pulse-chase studies as well as immunocytochemistry. Most of the newly synthesized PMP22 in Schwann cells is rapidly degraded in the endoplasmic reticulum. Only a small proportion of the total PMP22 acquires complex glycosylation and accumulates in the Golgi compartment. This material is translocated to the Schwann cell membrane in detectable amounts only when axonal contact and Myelination occur. Myelination does not, however, alter the rapid turnover of PMP22 in Schwann cells. PMP22 may therefore be a unique Myelin Protein in that axonal contact promotes its insertion into the Schwann cell membrane and Myelin without altering its rapid turnover rate within the cell.
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Peripheral Myelin Protein 22: facts and hypotheses.
Journal of Neuroscience Research, 1995Co-Authors: Ueli Suter, G. J. SnipesAbstract:Mutations affecting the peripheral Myelin Protein 22 (PMP22) gene are associated with inherited motor and sensory neuropathies in mouse (Trembler and Trembler-J) and human (Charcot-Marie-Tooth disease type 1A and Dejerine-Sottas syndrome). Although genetic studies have established a critical role of PMP22 in the formation and/or maintenance of Myelin in the peripheral nervous system, the biological function of PMP22 in Myelin and in non-Myelin forming cells remains largely enigmatic. In this Mini-Review, we will summarize the current knowledge about PMP22 and discuss its hypothetical function(s) in a broad context.
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a leucine to proline mutation in the putative first transmembrane domain of the 22 kda peripheral Myelin Protein in the trembler j mouse
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Ueli Suter, G. J. Snipes, A A Welcher, J J Moskow, B Kosaras, Richard L Sidman, A M Buchberg, Eric M. ShooterAbstract:Peripheral Myelin Protein PMP-22 is a potential growth-regulating Myelin Protein that is expressed by Schwann cells and predominantly localized in compact peripheral Myelin. A point mutation in the Pmp-22 gene of inbred trembler (Tr) mice was identified and proposed to be responsible for the Tr phenotype, which is characterized by paralysis of the limbs as well as tremors and transient seizures. In support of this hypothesis, we now report the fine mapping of the Pmp-22 gene to the immediate vicinity of the Tr locus on mouse chromosome 11. Furthermore, we have found a second point mutation in the Pmp-22 gene of trembler-J (TrJ) mice, which results in the substitution of a leucine residue by a proline residue in the putative first transmembrane region of the PMP-22 polypeptide. Tr and TrJ were previously mapped genetically as possible allelic mutations giving rise to similar, but not identical, phenotypes. This finding is consistent with the discovery of two different mutations in physicochemically similar domains of the PMP-22 Protein. Our results strengthen the hypothesis that mutations in the Pmp-22 gene can lead to heterogeneous forms of peripheral neuropathies and offer clues toward possible explanations for the dominant inheritance of these disorders.
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characterization of a novel peripheral nervous system Myelin Protein pmp 22 sr13
Journal of Cell Biology, 1992Co-Authors: G. J. Snipes, Ueli Suter, A A Welcher, Eric M. ShooterAbstract:We have recently described a novel cDNA, SR13 (Welcher, A. A., U. Suter, M. De Leon, G. J. Snipes, and E. M. Shooter. 1991. Proc. Natl. Acad. Sci. USA. 88:7195-7199), that is repressed after sciatic nerve crush injury and shows homology to both the growth arrest-specific mRNA, gas3 (Manfioletti, G., M. E. Ruaro, G. Del Sal, L. Philipson, and C. Schneider, 1990. Mol. Cell Biol. 10:2924-2930), and to the Myelin Protein, PASII (Kitamura, K., M. Suzuki, and K. Uyemura. 1976. Biochim. Biophys. Acta. 455:806-816). In this report, we show that the 22-kD SR13 Protein is expressed in the compact portion of essentially all Myelinated fibers in the peripheral nervous system. Although SR13 mRNA was found in the central nervous system, no corresponding SR13 Protein could be detected by either immunoblot analysis or by immunohistochemistry. Northern and immunoblot analysis of SR13 mRNA and Protein expression during development of the peripheral nervous system reveal a pattern similar to other Myelin Proteins. Furthermore, we demonstrate by in situ mRNA hybridization on tissue sections and on individual nerve fibers that SR13 mRNA is produced predominantly by Schwann cells. We conclude that the SR13 Protein is apparently exclusively expressed in the peripheral nervous system where it is a major component of Myelin. Thus, we propose the name Peripheral Myelin Protein-22 (PMP-22) for the Proteins and cDNA previously designated PASII, SR13, and gas3.
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Characterization of a novel peripheral nervous system Myelin Protein (PMP-22/SR13)
Journal of Cell Biology, 1992Co-Authors: G. J. Snipes, Ueli Suter, A A Welcher, Eric M. ShooterAbstract:We have recently described a novel cDNA, SR13 (Welcher, A. A., U. Suter, M. De Leon, G. J. Snipes, and E. M. Shooter. 1991. Proc. Natl. Acad. Sci. USA. 88:7195-7199), that is repressed after sciatic nerve crush injury and shows homology to both the growth arrest-specific mRNA, gas3 (Manfioletti, G., M. E. Ruaro, G. Del Sal, L. Philipson, and C. Schneider, 1990. Mol. Cell Biol. 10:2924-2930), and to the Myelin Protein, PASII (Kitamura, K., M. Suzuki, and K. Uyemura. 1976. Biochim. Biophys. Acta. 455:806-816). In this report, we show that the 22-kD SR13 Protein is expressed in the compact portion of essentially all Myelinated fibers in the peripheral nervous system. Although SR13 mRNA was found in the central nervous system, no corresponding SR13 Protein could be detected by either immunoblot analysis or by immunohistochemistry. Northern and immunoblot analysis of SR13 mRNA and Protein expression during development of the peripheral nervous system reveal a pattern similar to other Myelin Proteins. Furthermore, we demonstrate by in situ mRNA hybridization on tissue sections and on individual nerve fibers that SR13 mRNA is produced predominantly by Schwann cells. We conclude that the SR13 Protein is apparently exclusively expressed in the peripheral nervous system where it is a major component of Myelin. Thus, we propose the name Peripheral Myelin Protein-22 (PMP-22) for the Proteins and cDNA previously designated PASII, SR13, and gas3.
Ronald L. Schnaar - One of the best experts on this subject based on the ideXlab platform.
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enhanced binding of the neural siglecs Myelin associated glycoProtein and schwann cell Myelin Protein to chol 1 α series gangliosides and novel sulfated chol 1 analogs
Journal of Biological Chemistry, 1999Co-Authors: Brian E Collins, Naoki Sawada, Hideharu Ishida, Makoto Kiso, Ronald L. SchnaarAbstract:Abstract Extended glycoconjugate binding specificities of three sialic acid-dependent immunoglobulin-like family member lectins (siglecs), Myelin-associated glycoProtein (MAG), Schwann cell Myelin Protein (SMP), and sialoadhesin, were compared by measuring siglec-mediated cell adhesion to immobilized gangliosides. Synthetic gangliosides bearing the α-series determinant (NeuAc α2,6-linked to GalNAc on a gangliotetraose core) were tested, including GD1α (IV3NeuAc, III6NeuAc-Gg4OseCer), GD1α with modified sialic acid residues at the III6-position, and the “Chol-1” gangliosides GT1aα (IV3NeuAc, III6NeuAc, II3NeuAc-Gg4OseCer) and GQ1bα (IV3NeuAc, III6NeuAc, II3(NeuAc)2-Gg4OseCer). The α-series gangliosides displayed enhanced potency for MAG- and SMP-mediated cell adhesion (GQ1bα > GT1aα, GD1α > GT1b, GD1a ≫ GM1 (nonbinding)), whereas sialoadhesin-mediated adhesion was comparable with α-series and non-α-series gangliosides. GD1α derivatives with modified sialic acids (7-, 8-, or 9-deoxy) or sulfate (instead of sialic acid) at the III6-position supported adhesion comparable with that of GD1α. Notably, a novel GT1aα analog with sulfates at two internal sites of sialylation (NeuAcα2,3Galβ1,4GalNAc-6-sulfateβ1, 4Gal3-sulfateβ1,4Glcβ1,1′ceramide) was the most potent siglec-binding structure tested to date (10-fold more potent than GT1aα in supporting MAG and SMP binding). Together with prior studies, these data indicate that MAG and SMP display an extended structural specificity with a requirement for a terminal α2,3-linked NeuAc and great enhancement by nearby precisely spaced anionic charges.
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Multivalent ganglioside and sphingosine conjugates modulate Myelin Protein kinases.
Biochimica et Biophysica Acta, 1997Co-Authors: James A. Mahoney, Ronald L. SchnaarAbstract:Gangliosides, added exogenously at concentrations of 10-100 microM, inhibit intrinsic Protein kinase activities in purified rat brain Myelin. Multivalent neoganglioProteins--gangliosides covalently attached, via their lipid moieties, to bovine serum albumin--were much more potent, inhibiting Myelin Protein phosphorylation half-maximally at a concentration of 100 nM. Different ganglioside conjugates varied 10-fold in inhibitory potency; GT1b-conjugates being the most potent and GM3-conjugates being the least. Conjugates of ganglioside oligosaccharides, lacking the lipid moiety, did not inhibit Myelin Protein phosphorylation, whereas conjugates of sphingosine inhibited nearly as potently as GT1b conjugates. Conjugate-mediated inhibition of Myelin Protein phosphorylation was due to inhibition of a Protein serine kinase activity rather than activation of a phosphatase activity. We conclude that (i) clustered gangliosides or sphingosine are potent Myelin Protein kinase inhibitors, and (ii) sphingolipid metabolism is not required for Myelin Protein kinase inhibition. In contrast to their effects on Myelin Protein phosphorylation, ganglioside conjugates stimulated phosphorylation of a presumptive axon membrane Protein. The data support the conclusion that gangliosides and other sphingolipids, when appropriately clustered, are potent modulators of central nervous system Protein phosphorylation.
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binding specificities of the sialoadhesin family of i type lectins sialic acid linkage and substructure requirements for binding of Myelin associated glycoProtein schwann cell Myelin Protein and sialoadhesin
Journal of Biological Chemistry, 1997Co-Authors: Brian E Collins, Makoto Kiso, Akira Hasegawa, Michael B Tropak, John C Roder, Paul R Crocker, Ronald L. SchnaarAbstract:Abstract The carbohydrate binding specificities of three sialoadhesins, a subgroup of I-type lectins (immunoglobulin superfamily lectins), were compared by measuring lectin-transfected COS cell adhesion to natural and synthetic gangliosides. The neural sialoadhesins, Myelin-associated glycoProtein (MAG) and Schwann cell Myelin Protein (SMP), had similar and stringent binding specificities. Each required an α2,3-linked sialic acid on the terminal galactose of a neutral saccharide core, and they shared the following rank-order potency of binding: GQ1bα ≫ GD1a = GT1b ≫ GM3 = GM4 ≫ GM1, GD1b, GD3, GQ1b(nonbinders). In contrast, sialoadhesin had less exacting specificity, binding to gangliosides that bear either terminal α2,3- or α2,8-linked sialic acids with the following rank-order potency of binding: GQ1bα > GD1a = GD1b = GT1b = GM3 = GM4 > GD3= GQ1b ≫ GM1 (nonbinder). CD22 did not bind to any ganglioside tested. Binding of MAG, SMP, and sialoadhesin was abrogated by chemical modification of either the sialic acid carboxylic acid group or glycerol side chain on a target ganglioside. Synthetic ganglioside GM3 derivatives further distinguished lectin binding specificities. Deoxy and/or methoxy derivatives of the 4-, 7-, 8-, or 9-position of sialic acid attenuated or eliminated binding of MAG, as did replacement of the sialic acid acetamido group with a hydroxyl. In contrast, the 4- and 7-deoxysialic acid derivatives supported sialoadhesin binding at near control levels (the other derivatives did not support binding). These data are consistent with sialoadhesin binding to one face of the sialic acid moiety, whereas MAG (and SMP) may have more complex binding sites or may bind sialic acids only in the context of more restricted oligosaccharide conformations.
