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1.
Proc Natl Acad Sci U S A ; 115(6): E1319-E1328, 2018 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-29351992

RESUMEN

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in xenobiotic metabolism. Plexiform neurofibromas (PNFs) can transform into malignant peripheral nerve sheath tumors (MPNSTs) that are resistant to existing therapies. These tumors are primarily composed of Schwann cells. In addition to neurofibromatosis type 1 (NF1) gene inactivation, further genetic lesions are required for malignant transformation. We have quantified the mRNA expression levels of AHR and its associated genes in 38 human samples. We report that AHR and the biosynthetic enzymes of its endogenous ligand are overexpressed in human biopsies of PNFs and MPNSTs. We also detect a strong nuclear AHR staining in MPNSTs. The inhibition of AHR by siRNA or antagonists, CH-223191 and trimethoxyflavone, induces apoptosis in human MPNST cells. Since AHR dysregulation is observed in these tumors, we investigate AHR involvement in Schwann cell physiology. Hence, we studied the role of AHR in myelin structure and myelin gene regulation in Ahr-/- mice during myelin development. AHR ablation leads to locomotion defects and provokes thinner myelin sheaths around the axons. We observe a dysregulation of myelin gene expression and myelin developmental markers in Ahr-/- mice. Interestingly, AHR does not directly bind to myelin gene promoters. The inhibition of AHR in vitro and in vivo increased ß-catenin levels and stimulated the binding of ß-catenin on myelin gene promoters. Taken together, our findings reveal an endogenous role of AHR in peripheral myelination and in peripheral nerve sheath tumors. Finally, we suggest a potential therapeutic approach by targeting AHR in nerve tumors.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Transformación Celular Neoplásica/patología , Regulación Neoplásica de la Expresión Génica , Vaina de Mielina/patología , Neoplasias de la Vaina del Nervio/patología , Receptores de Hidrocarburo de Aril/fisiología , Animales , Apoptosis , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Células Cultivadas , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Vaina de Mielina/metabolismo , Neoplasias de la Vaina del Nervio/genética , Neoplasias de la Vaina del Nervio/metabolismo , Transducción de Señal
2.
Proc Natl Acad Sci U S A ; 112(24): 7587-92, 2015 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-26023184

RESUMEN

The identification of new pathways governing myelination provides innovative avenues for remyelination. Liver X receptors (LXRs) α and ß are nuclear receptors activated by oxysterols that originated from the oxidation of cholesterol. They are crucial for cholesterol homeostasis, a major lipid constituent of myelin sheaths that are formed by oligodendrocytes. However, the role of LXRs in myelin generation and maintenance is poorly understood. Here, we show that LXRs are involved in myelination and remyelination processes. LXRs and their ligands are present in oligodendrocytes. We found that mice invalidated for LXRs exhibit altered motor coordination and spatial learning, thinner myelin sheaths, and reduced myelin gene expression. Conversely, activation of LXRs by either 25-hydroxycholesterol or synthetic TO901317 stimulates myelin gene expression at the promoter, mRNA, and protein levels, directly implicating LXRα/ß in the transcriptional control of myelin gene expression. Interestingly, activation of LXRs also promotes oligodendroglial cell maturation and remyelination after lysolecithin-induced demyelination of organotypic cerebellar slice cultures. Together, our findings represent a conceptual advance in the transcriptional control of myelin gene expression and strongly support a new role of LXRs as positive modulators in central (re)myelination processes.


Asunto(s)
Cerebelo/fisiología , Vaina de Mielina/fisiología , Receptores Nucleares Huérfanos/fisiología , Animales , Diferenciación Celular/efectos de los fármacos , Cerebelo/citología , Cerebelo/efectos de los fármacos , Colesterol/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Homeostasis , Hidrocarburos Fluorados/farmacología , Hidroxicolesteroles/farmacología , Receptores X del Hígado , Masculino , Ratones , Ratones Noqueados , Vaina de Mielina/efectos de los fármacos , Vaina de Mielina/genética , Oligodendroglía/citología , Oligodendroglía/efectos de los fármacos , Oligodendroglía/metabolismo , Técnicas de Cultivo de Órganos , Receptores Nucleares Huérfanos/agonistas , Receptores Nucleares Huérfanos/deficiencia , Regiones Promotoras Genéticas , Desempeño Psicomotor/efectos de los fármacos , Desempeño Psicomotor/fisiología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Aprendizaje Espacial/efectos de los fármacos , Aprendizaje Espacial/fisiología , Sulfonamidas/farmacología
3.
Diabetes ; 69(3): 448-464, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31882567

RESUMEN

Diabetes triggers peripheral nerve alterations at a structural and functional level, collectively referred to as diabetic peripheral neuropathy (DPN). This work highlights the role of the liver X receptor (LXR) signaling pathway and the cross talk with the reactive oxygen species (ROS)-producing enzyme NADPH oxidase-4 (Nox4) in the pathogenesis of DPN. Using type 1 diabetic (T1DM) mouse models together with cultured Schwann cells (SCs) and skin biopsies from patients with type 2 diabetes (T2DM), we revealed the implication of LXR and Nox4 in the pathophysiology of DPN. T1DM animals exhibit neurophysiological defects and sensorimotor abnormalities paralleled by defective peripheral myelin gene expression. These alterations were concomitant with a significant reduction in LXR expression and increase in Nox4 expression and activity in SCs and peripheral nerves, which were further verified in skin biopsies of patients with T2DM. Moreover, targeted activation of LXR or specific inhibition of Nox4 in vivo and in vitro to attenuate diabetes-induced ROS production in SCs and peripheral nerves reverses functional alteration of the peripheral nerves and restores the homeostatic profiles of MPZ and PMP22. Taken together, our findings are the first to identify novel, key mediators in the pathogenesis of DPN and suggest that targeting LXR/Nox4 axis is a promising therapeutic approach.


Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Neuropatías Diabéticas/metabolismo , Receptores X del Hígado/metabolismo , NADPH Oxidasa 4/metabolismo , Células de Schwann/metabolismo , Anciano , Anciano de 80 o más Años , Animales , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Neuropatías Diabéticas/etiología , Femenino , Humanos , Hidrocarburos Fluorados/farmacología , Receptores X del Hígado/agonistas , Masculino , Ratones , Proteínas de la Mielina/genética , NADPH Oxidasa 4/antagonistas & inhibidores , Pirazoles/farmacología , Pirazolonas , Piridinas/farmacología , Piridonas , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Sulfonamidas/farmacología
4.
Sci Rep ; 8(1): 2524, 2018 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-29410501

RESUMEN

Reactive oxygen species (ROS) modify proteins and lipids leading to deleterious outcomes. Thus, maintaining their homeostatic levels is vital. This study highlights the endogenous role of LXRs (LXRα and ß) in the regulation of oxidative stress in peripheral nerves. We report that the genetic ablation of both LXR isoforms in mice (LXRdKO) provokes significant locomotor defects correlated with enhanced anion superoxide production, lipid oxidization and protein carbonylation in the sciatic nerves despite the activation of Nrf2-dependant antioxidant response. Interestingly, the reactive oxygen species scavenger N-acetylcysteine counteracts behavioral, electrophysical, ultrastructural and biochemical alterations in LXRdKO mice. Furthermore, Schwann cells in culture pretreated with LXR agonist, TO901317, exhibit improved defenses against oxidative stress generated by tert-butyl hydroperoxide, implying that LXRs play an important role in maintaining the redox homeostasis in the peripheral nervous system. Thus, LXR activation could be a promising strategy to protect from alteration of peripheral myelin resulting from a disturbance of redox homeostasis in Schwann cell.


Asunto(s)
Homeostasis , Receptores X del Hígado/fisiología , Vaina de Mielina/metabolismo , Estrés Oxidativo , Células de Schwann , Nervio Ciático , Animales , Línea Celular , Hidrocarburos Fluorados/química , Metabolismo de los Lípidos , Receptores X del Hígado/antagonistas & inhibidores , Receptores X del Hígado/genética , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 2 Relacionado con NF-E2/metabolismo , Oxidación-Reducción , Carbonilación Proteica , Especies Reactivas de Oxígeno/metabolismo , Células de Schwann/citología , Células de Schwann/metabolismo , Nervio Ciático/citología , Nervio Ciático/metabolismo , Sulfonamidas/química , terc-Butilhidroperóxido/química
5.
Antioxid Redox Signal ; 27(3): 168-183, 2017 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-27788593

RESUMEN

AIMS: Paraquat (PQT), a redox-active herbicide, is a free radical-producing molecule, causing damage particularly to the nervous system; thus, it is employed as an animal model for Parkinson's disease. However, its impact on peripheral nerve demyelination is still unknown. Our aim is to decipher the influence of PQT-induced reactive oxygen species (ROS) production on peripheral myelin. RESULTS: We report that PQT provokes severe locomotor and sensory defects in mice. PQT elicited an oxidative stress in the nerve, resulting in an increase of lipid peroxidation and protein carbonylation, despite the induction of nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant defenses. We observed a dramatic disorganization of myelin sheaths in the sciatic nerves, dysregulation of myelin gene expression, and aggregation of myelin proteins, a hallmark of demyelination. PQT altered myelin gene expression via liver X receptor (LXR) signaling, a negative regulator of peripheral myelin gene expression through its dialog with the Wnt/ß-catenin pathway. PQT prevented ß-catenin binding on myelin gene promoters, resulting in the inhibition of Wnt/ß-catenin-dependent myelin gene expression. Wnt pathway activation by LiCl dampened the deleterious effects of PQT. LiCl blocked PQT-induced oxidative stress and reduced Schwann cell death. LiCl+PQT-treated mice had normal sensorimotor behaviors and a usual nerve structure. INNOVATION: We reveal that PQT damages the sciatic nerve by generating an oxidative stress, dysregulating LXR and Wnt/ß-catenin pathways. The activation of Wnt signaling by LiCl reduced the deleterious effects of PQT on the nerve. CONCLUSION: We demonstrate that PQT instigates peripheral nerve demyelinating neuropathies by enhancing ROS production and deregulating LXR and Wnt pathways. Stimulating Wnt pathway could be a therapeutic strategy for neuropathy treatment. Antioxid. Redox Signal. 27, 168-183.


Asunto(s)
Enfermedades Desmielinizantes/inducido químicamente , Herbicidas/toxicidad , Receptores X del Hígado/metabolismo , Vaina de Mielina/efectos de los fármacos , Paraquat/toxicidad , Vía de Señalización Wnt/efectos de los fármacos , Animales , Línea Celular , Enfermedades Desmielinizantes/etiología , Enfermedades Desmielinizantes/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Proteínas de la Mielina/química , Proteínas de la Mielina/genética , Proteínas de la Mielina/metabolismo , Vaina de Mielina/metabolismo , Estrés Oxidativo , Agregación Patológica de Proteínas , Carbonilación Proteica/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Células de Schwann/citología , Células de Schwann/efectos de los fármacos , Células de Schwann/metabolismo
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