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1.
Nat Commun ; 9(1): 3025, 2018 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-30072689

RESUMO

In patients with Charcot-Marie-Tooth disease 1A (CMT1A), peripheral nerves display aberrant myelination during postnatal development, followed by slowly progressive demyelination and axonal loss during adult life. Here, we show that myelinating Schwann cells in a rat model of CMT1A exhibit a developmental defect that includes reduced transcription of genes required for myelin lipid biosynthesis. Consequently, lipid incorporation into myelin is reduced, leading to an overall distorted stoichiometry of myelin proteins and lipids with ultrastructural changes of the myelin sheath. Substitution of phosphatidylcholine and phosphatidylethanolamine in the diet is sufficient to overcome the myelination deficit of affected Schwann cells in vivo. This treatment rescues the number of myelinated axons in the peripheral nerves of the CMT rats and leads to a marked amelioration of neuropathic symptoms. We propose that lipid supplementation is an easily translatable potential therapeutic approach in CMT1A and possibly other dysmyelinating neuropathies.


Assuntos
Doença de Charcot-Marie-Tooth/terapia , Metabolismo dos Lipídeos , Bainha de Mielina/metabolismo , Animais , Axônios/metabolismo , Axônios/ultraestrutura , Gorduras na Dieta/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/biossíntese , Bainha de Mielina/ultraestrutura , Fosfolipídeos/metabolismo , Ratos Transgênicos , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Células de Schwann/patologia
2.
Neuromolecular Med ; 8(1-2): 205-16, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16775377

RESUMO

The most frequent genetic subtype of Charcot-Marie-Tooth disease is CMT1A, linked to chromosome 17p11.2. In the majority of cases, CMT1A is a gene dosage disease associated with a 1.5 Mb large genomic duplication. Transgenic models with extra copies of the Pmp22 gene have provided formal proof that overexpression of only this candidate gene is sufficent to cause peripheral demyelination, onion bulb formation, secondary axonal loss, and progressive muscle atrophy, the pathological hallmarks of CMT1A. The transgenic CMT rat with about 1.6-fold PMP22 overexpression exhibits clinical abnormalities, such as reduced nerve conduction velocity and lower grip strength that mimick findings in CMT1A patients. Also transgenic mice, carrying yeast artifical chromosomes as Pmp22 transgenes, demonstrate the variability of disease expression as a function of increased gene dosage. Recently, the first rational experimental therapies of CMT1A were tested, using transgenic animal models. In one proof-of-principle study with the CMT rat, a synthetic antagonist of the nuclear progesterone receptor was shown to reduce PMP22 overexpression and to ameliorate the clinical severity. In another study, administration of ascorbic acid, an essential factor of in vitro myelination, prolonged the survival and restored myelination of a dysmyelinated mouse model. Application of gene expression analysis to nerve biopsies that are readily available from such CMT1A animal models might identify additional pharmacological targets.


Assuntos
Doença de Charcot-Marie-Tooth/fisiopatologia , Modelos Animais de Doenças , Animais , Animais Geneticamente Modificados , Antioxidantes/uso terapêutico , Ácido Ascórbico/uso terapêutico , Doença de Charcot-Marie-Tooth/patologia , Doença de Charcot-Marie-Tooth/terapia , Cromossomos Humanos Par 17 , Dosagem de Genes , Humanos , Proteínas da Mielina/genética , Proteínas da Mielina/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Progesterona/antagonistas & inibidores , Progesterona/uso terapêutico
3.
J Neurosci ; 21(3): 920-33, 2001 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-11157078

RESUMO

The expression of the 330 kDa AN2 glycoprotein was studied in the rodent peripheral nervous system. AN2 is expressed by immature Schwann cells in vitro and in vivo and downregulated as the cells upregulate myelin genes. A subpopulation of nonmyelinating Schwann cells in the adult sciatic nerve retains expression of AN2. In rat sciatic nerve crushes, where Schwann cell numbers increase after initial axonal loss and markers of immature Schwann cells show an upregulation, no increased expression of AN2 was observed. In contrast, AN2 expression was upregulated in nerves from peripheral myelin protein-22-transgenic rats, where immature Schwann cells expand without axonal loss. Furthermore, coculture with neurons upregulated AN2 expression on Schwann cells in vitro. Polyclonal antibodies against AN2 inhibited the migration of an immortalized Schwann cell clone in an in vitro migration assay, and the purified AN2 protein was shown to be neither inhibitory nor permissive for outgrowing dorsal root ganglion neurites. AN2 is thus a novel marker for the Schwann cell lineage. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis of purified AN2 from early postnatal mouse brain demonstrated that AN2 is the murine homolog of the rat NG2 proteoglycan.


Assuntos
Antígenos de Diferenciação/biossíntese , Antígenos/biossíntese , Proteínas de Bactérias , Doença de Charcot-Marie-Tooth/genética , Bainha de Mielina/metabolismo , Proteoglicanas/biossíntese , Células de Schwann/metabolismo , Animais , Antígenos/análise , Antígenos/genética , Química Encefálica , Linhagem da Célula/fisiologia , Movimento Celular , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Gânglios Espinais/citologia , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Camundongos , Camundongos Endogâmicos , Proteínas da Mielina/genética , Neuritos/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Sistema Fosfotransferase de Açúcar do Fosfoenolpiruvato , Processamento de Proteína Pós-Traducional/genética , Proteoglicanas/análise , Proteoglicanas/genética , Ratos , Ratos Wistar , Células de Schwann/citologia , Nervo Isquiático/fisiologia , Homologia de Sequência de Aminoácidos , Degeneração Walleriana/metabolismo
4.
J Neurosci ; 20(11): 4120-8, 2000 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-10818147

RESUMO

We have generated previously transgenic rats that overexpress peripheral myelin protein 22 (PMP22) in Schwann cells. In the nerves of these animals, Schwann cells have segregated with axons to the normal 1:1 ratio but remain arrested at the promyelinating stage, apparently unable to elaborate myelin sheaths. We have examined gene expression of these dysmyelinating Schwann cells using semiquantitative reverse transcription-PCR and immunofluorescence analysis. Unexpectedly, Schwann cell differentiation appears to proceed normally at the molecular level when monitored by the expression of mRNAs encoding major structural proteins of myelin. Furthermore, an aberrant coexpression of early and late Schwann cell markers was observed. PMP22 itself acquires complex glycosylation, suggesting that trafficking of the myelin protein through the endoplasmic reticulum is not significantly impaired. We suggest that PMP22, when overexpressed, accumulates in a late Golgi-cell membrane compartment and uncouples myelin assembly from the underlying program of Schwann cell differentiation.


Assuntos
Proteínas da Mielina/genética , Bainha de Mielina/fisiologia , Células de Schwann/fisiologia , Animais , Animais Geneticamente Modificados , Bromodesoxiuridina , Diferenciação Celular/fisiologia , Retículo Endoplasmático/ultraestrutura , Imunofluorescência , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Glicosilação , Homozigoto , Masculino , Proteínas da Mielina/biossíntese , Bainha de Mielina/ultraestrutura , Fibras Nervosas/fisiologia , RNA/biossíntese , RNA/genética , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células de Schwann/ultraestrutura
5.
Ann N Y Acad Sci ; 883: 254-61, 1999 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-10586250

RESUMO

We have generated a transgenic rat model of Charcot-Marie-Tooth disease type 1A (CMT1A) providing formal proof that this neuropathy can be caused by increased expression of peripheral myelin protein-22 (PMP22). Heterozygous PMP22-transgenic rats develop muscle weakness and gait abnormalities as well as reduced nerve conduction velocities and EMG abnormalities, which closely resemble recordings in patients with CMT1A. Dys- and demyelination, Schwann cell hypertrophy, and "onion bulb" formation are also similar to findings in humans. When bred to homozygosity, transgenic rats completely fail to elaborate myelin, but all myelin-forming Schwann cells segregate with axons in the normal one-to-one ratio. Although arrested at this "promyelin" stage, differentiation proceeds in homozygous rats at the molecular level, as demonstrated by high-level expression of myelin structural genes. Intracellular trafficking of the wild-type protein is not visibly impaired, even when strongly overexpressed, suggesting that PMP22 blocks myelin assembly in a late Golgi/cell membrane compartment of the affected Schwann cell.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Proteínas da Mielina/genética , Bainha de Mielina/patologia , Animais , Animais Geneticamente Modificados , Humanos , Proteínas da Mielina/fisiologia , Bainha de Mielina/genética , Ratos
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