Overloaded Endoplasmic Reticulum–Golgi Compartments, a Possible Pathomechanism of Peripheral Neuropathies Caused by Mutations of the Peripheral Myelin Protein PMP22

D’Urso, Donatella; Prior, Reinhard; Greiner–Petter, Regine; Gabreëls-Festen, A.A.W.M.; Müller, Hans

doi:10.1523/jneurosci.18-02-00731.1998

Cited by 110 publications

(87 citation statements)

References 30 publications

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“…All of the family members have similar primary and secondary structures, with 4 relatively conserved transmembrane regions and 2 significant extracellular loops. 29,30 Although the endogenous functions of this family remain enigmatic, on disruption, many of the genes yield dramatic phenotypes. For example, EMP1 was initially isolated as a gene expressed in brain tumors but not in normal brain.…”

Section: Discussionmentioning

confidence: 99%

Epithelial membrane protein 2, a 4-transmembrane protein that suppresses B-cell lymphoma tumorigenicity

Wang

Wadehra

Fisk

et al. 2001

Blood

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A murine homologue of the epithelial membrane protein 2 (EMP2) gene was identified in a search for genes associated with B-cell lymphoma tumorigenicity by using suppression subtractive hybridization. Expression of EMP2 messenger RNA in primary mouse tissues was limited to certain epithelial cell types and the peritoneal lymphoid compartment. EMP2 was expressed in the poorly tumorigenic DAC B-lymphoma cell line but was significantly down-regulated in a subline selected for in vivo tumor formation in Balb/c mice. Recombinant restoration of EMP2 expression in the subline suppressed its tumorigenicity, suggesting that loss of EMP2 was a causal factor in the malignant phenotype. Recombinant overexpression of EMP2 was studied in B lymphoma and NIH3T3 cells. EMP2 in both cell types induced cell death on serum deprivation. EMP2-induced cell death correlated with the expression level of EMP2 protein and was prevented by caspase inhibitors Z-VAD and Z-DEVD. These findings for the first time describe an apoptotic effect of a GAS3 family gene in lymphocytes. They also suggest that EMP2 may influence B-lymphoma tumorigenicity through a functional tumor suppressor phenotype. ( IntroductionB-cell lymphoma is among the more common classes of human malignancies, with the number of cases doubling over the past 20 years. Lymphomas are generally multifocal at the time of diagnosis and progress over time to more aggressive phenotypes, including invasion of extranodal sites and resistance to therapy. 1 A number of molecular targets have been identified in natural B-cell lymphomagenesis (eg, c-myc, bcl-2, bcl-6) with important roles in the molecular pathophysiology of corresponding classes of lymphomas (Burkitt, follicular, and diffuse large cell lymphomas, respectively). 2,3 However, in vivo and in vitro experimentation has shown that activation of these genes individually is insufficient for a malignant phenotype. Relatively few collaborating genes have been identified for the progression to malignancy, notably those involving checkpoint control and genomic stability. [4][5][6][7] The malignant phenotype involves the roles of several biologic traits in addition to growth control. 8 For example, in tumors arising in breast and prostate, invasion and metastasis are associated with altered expression of molecules affecting tumor-stromal and -endothelial interactions: matrix proteinases and proteinase inhibitors, and the integrin receptors. 9,10 In B-cell lymphomagenesis, there is also evidence for host-tumor interactions involving immune function either directly or through its action against lymphomagenic microbial infection. 11 To characterize host-tumor interaction in B-cell lymphomagenesis, our laboratory previously established a murine model system. 12-14 The DAC cell line was generated from the spontaneous in vitro outgrowth of splenic lymphocytes. Thus, DAC cells were not selected for in vivo growth and generally failed to form tumors in syngeneic immunocompetent mice. From the exceptional DAC tumors that did occur, malignant v...

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Section: Discussionmentioning

confidence: 99%

Epithelial membrane protein 2, a 4-transmembrane protein that suppresses B-cell lymphoma tumorigenicity

Wang

Wadehra

Fisk

et al. 2001

Blood

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“…Recently, we have studied two PMP22 point mutations, L16P and G150D, carried by the spontaneous mouse mutants Trembler J and Trembler and found in patients affected by CMT1A and DSS, respectively (Valentijn et al, 1992;Ionasescu et al, 1997). For both mutants, we showed that the protein is not transported to the plasma membrane but accumulates in the endoplasmic reticulum and Golgi compartments (D'Urso et al, 1998). When the mutant and the wild-type PMP22 coexist, only the nonmutated protein is inserted into the myelin membrane, resulting in a net decrease in the amount of functional protein.…”

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confidence: 93%

Peripheral Myelin Protein 22 and Protein Zero: a Novel Association in Peripheral Nervous System Myelin

1999

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Mutations found in the two major glycosylated transmembrane proteins of the PNS myelin, the peripheral myelin protein zero (P0) and peripheral myelin protein 22 (PMP22), have been independently associated with the most common hereditary demyelinating peripheral neuropathies. Genotype-phenotype correlations in humans and transgenic animals have provided functional evidence that P0 and PMP22 are involved in formation and maintenance of compact myelin. Here, we demonstrate for the first time that P0 and PMP22 proteins form complexes in the myelin membrane, as shown by coimmunoprecipitation experiments, and that glycosylation is not involved in mediating these interactions. Complex formation was also detected when the two proteins were coexpressed in heterologous cells. In transfected cells, P0 and PMP22 are recruited and colocalize at the apposed plasma membranes of expressors as shown by confocal microscopy. These findings provide a new basis for a better understanding of myelin assembly and of the pathomechanisms involved in demyelinating peripheral neuropathies. Furthermore, these results propose a possible explanation why alterations in either of these molecules are sufficient to destabilize the myelin structure and cause a similar disease phenotype.

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“…Many PMP-22 mutations are retained intracellularly (9)(10)(11)(12) and appear to belong to a growing class of mutations termed ''endoplasmic reticulum (ER) retention mutations'' that are recognized by ER resident-folding proteins, molecular chaperones, and͞or other enzymes that serve to monitor the fidelity of protein synthesis and macromolecular assembly (13,14). Among ER retention diseases, however, heritable neuropathies caused by PMP-22 mutation or overexpression are unique because they are dominant gain-of-function diseases (15).…”

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confidence: 99%

Association of calnexin with mutant peripheral myelin protein-22 ex vivo : A basis for “gain-of-function” ER diseases

Dickson

Bergeron

Shames

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

108

110

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The function of PMP-22 is unknown, but roles in cell growth, apoptosis, higher order macromolecular structure, and intracellular signaling have been proposed (1). Intrachromosomal duplications (2) and deletions (3) encompassing PMP-22 cause Charcot-MarieTooth disease and hereditary neuropathy with liability to pressure palsies, respectively. In addition, point mutations have been found in patients with Charcot-Marie-Tooth disease, hereditary neuropathy with liability to pressure palsies, and DejerineSottas syndrome (4). Indeed, the first missense mutations to be identified in the PMP-22 gene were found in the Tr (5) and Tr-J (6) mice with identical point mutations shared between humans and mice (7, 8).Many PMP-22 mutations are retained intracellularly (9-12) and appear to belong to a growing class of mutations termed ''endoplasmic reticulum (ER) retention mutations'' that are recognized by ER resident-folding proteins, molecular chaperones, and͞or other enzymes that serve to monitor the fidelity of protein synthesis and macromolecular assembly (13,14). Among ER retention diseases, however, heritable neuropathies caused by PMP-22 mutation or overexpression are unique because they are dominant gain-of-function diseases (15).Here, transient and glucosylation-dependent association of PMP-22 with the ER chaperone calnexin (CNX) was observed. PMP-22 associated only with CNX. Formation of intracellular myelin-like figures (IMLFs) in transfected cells coincided with the cosequestration of CNX in a glucosylation dependent fashion. Similar intracellular myelin-like structures were present in the sciatic nerves of homozygous Tr-J mice. These results provide a mechanistic explanation for the human Charcot-Marie-Tooth disease secondary to the ER retention of mutant PMP-22 via the CNX cycle and provide an unexpected link between the gain-offunction phenotype of such diseases and sequestration of the resident ER lectin chaperone, CNX. Materials and MethodsMetabolic Labeling, Immunoprecipitations, and Western Blot Analysis.Metabolic labeling and pulse-chase of mouse sciatic nerves and immunoprecipitations for PMP-22 (16) as well as nondenaturing CNX immunoprecipitations, BiP immunoprecipitation, and ATP depletion of cell lysates have been described (17, 18). For sequential PMP-22 immunoprecipitations, lysates were first CNX immunoprecipitated as described (17) followed by resolubilization in 0.5% SDS in 50 mM Tris (pH 8.0) and PMP-22 immunoprecipitated in modified radioimmunoprecipitation assay buffer (50 mM Tris, pH 8.0͞150 mM NaCl͞1% deoxycholate containing 0.5% Nonidet P-40). Samples were electrophoresed, transferred to nitrocellulose membranes, and exposed to film by using the Kodak Biomax Transcreen LE system (NEN). For some experiments, sciatic nerves were pretreated with 1 mM castanospermine (SigmaAldrich) for 1 h at 37°C before and during metabolic labeling. Samples were then homogenized in 2% 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate lysis buffer containing 5 mM iodoacetamide and gels processed for fluo...

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Overloaded Endoplasmic Reticulum–Golgi Compartments, a Possible Pathomechanism of Peripheral Neuropathies Caused by Mutations of the Peripheral Myelin Protein PMP22

Cited by 110 publications

References 30 publications

Epithelial membrane protein 2, a 4-transmembrane protein that suppresses B-cell lymphoma tumorigenicity

Epithelial membrane protein 2, a 4-transmembrane protein that suppresses B-cell lymphoma tumorigenicity

Peripheral Myelin Protein 22 and Protein Zero: a Novel Association in Peripheral Nervous System Myelin

Association of calnexin with mutant peripheral myelin protein-22 ex vivo : A basis for “gain-of-function” ER diseases

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