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mGluR5 regulates REST/NRSF signaling through N-cadherin/ß-catenin complex in Huntington's disease.
de Souza, Jéssica M; Abd-Elrahman, Khaled S; Ribeiro, Fabiola M; Ferguson, Stephen S G.
Afiliación
  • de Souza JM; University of Ottawa Brain and Mind Institute and Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, K1H 8M5, Canada.
  • Abd-Elrahman KS; Department of Biochemistry and Immunology, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
  • Ribeiro FM; University of Ottawa Brain and Mind Institute and Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, K1H 8M5, Canada.
  • Ferguson SSG; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
Mol Brain ; 13(1): 118, 2020 08 28.
Article en En | MEDLINE | ID: mdl-32859226
Repressor element 1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is a transcription repressor and its expression is regulated by the Wnt pathway through ß-catenin. Metabotropic glutamate receptor 5 (mGluR5) signaling plays a key role in controlling neuronal gene expression. Interestingly, REST/NRSF nuclear translocation and signaling, as well as mGluR5 signaling are altered in the presence of mutant huntingtin. It remains unclear whether mGluR5 can modulate Wnt and REST/NRSF signaling under physiological conditions and whether this modulation is altered in Huntington's disease (HD). Using primary corticostriatal neurons derived from wild type mouse embryos, we find that targeting mGluR5 using the agonist, DHPG, or the negative allosteric modulator, CTEP, modulates REST/NRSF expression by regulating the assembly of N-cadherin/ ß-catenin complex in a Src kinase-dependent manner. We have validated our in vitro findings in vivo using two HD mouse models. Specifically, we show that pharmacological inhibition of mGluR5 in zQ175 mice and genetic ablation of mGluR5 in BACHD mice corrected the pathological activation of Src and rescued REST/NRSF-dependent signaling. Together, our data provide evidence that mGluR5 regulates REST/NRSF expression via the Wnt pathway and highlight the contribution of impaired REST/ NRSF signaling to HD pathology.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Represoras / Transducción de Señal / Cadherinas / Enfermedad de Huntington / Beta Catenina / Receptor del Glutamato Metabotropico 5 Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Mol Brain Asunto de la revista: BIOLOGIA MOLECULAR / CEREBRO Año: 2020 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Represoras / Transducción de Señal / Cadherinas / Enfermedad de Huntington / Beta Catenina / Receptor del Glutamato Metabotropico 5 Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Mol Brain Asunto de la revista: BIOLOGIA MOLECULAR / CEREBRO Año: 2020 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido