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Megalencephalic Leukoencephalopathy with Subcortical Cysts Disease-Linked MLC1 Protein Favors Gap-Junction Intercellular Communication by Regulating Connexin 43 Trafficking in Astrocytes

Astrocytes, the most numerous cells of the central nervous system, exert critical functions for brain homeostasis. To this purpose, astrocytes generate a highly interconnected intercellular network allowing rapid exchange of ions and metabolites through gap junctions, adjoined channels composed of h...

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Autores principales: Lanciotti, Angela, Brignone, Maria Stefania, Belfiore, Marcello, Columba-Cabezas, Sandra, Mallozzi, Cinzia, Vincentini, Olimpia, Molinari, Paola, Petrucci, Tamara Corinna, Visentin, Sergio, Ambrosini, Elena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348769/
https://www.ncbi.nlm.nih.gov/pubmed/32521795
http://dx.doi.org/10.3390/cells9061425
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author Lanciotti, Angela
Brignone, Maria Stefania
Belfiore, Marcello
Columba-Cabezas, Sandra
Mallozzi, Cinzia
Vincentini, Olimpia
Molinari, Paola
Petrucci, Tamara Corinna
Visentin, Sergio
Ambrosini, Elena
author_facet Lanciotti, Angela
Brignone, Maria Stefania
Belfiore, Marcello
Columba-Cabezas, Sandra
Mallozzi, Cinzia
Vincentini, Olimpia
Molinari, Paola
Petrucci, Tamara Corinna
Visentin, Sergio
Ambrosini, Elena
author_sort Lanciotti, Angela
collection PubMed
description Astrocytes, the most numerous cells of the central nervous system, exert critical functions for brain homeostasis. To this purpose, astrocytes generate a highly interconnected intercellular network allowing rapid exchange of ions and metabolites through gap junctions, adjoined channels composed of hexamers of connexin (Cx) proteins, mainly Cx43. Functional alterations of Cxs and gap junctions have been observed in several neuroinflammatory/neurodegenerative diseases. In the rare leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts (MLC), astrocytes show defective control of ion/fluid exchanges causing brain edema, fluid cysts, and astrocyte/myelin vacuolation. MLC is caused by mutations in MLC1, an astrocyte-specific protein of elusive function, and in GlialCAM, a MLC1 chaperon. Both proteins are highly expressed at perivascular astrocyte end-feet and astrocyte-astrocyte contacts where they interact with zonula occludens-1 (ZO-1) and Cx43 junctional proteins. To investigate the possible role of Cx43 in MLC pathogenesis, we studied Cx43 properties in astrocytoma cells overexpressing wild type (WT) MLC1 or MLC1 carrying pathological mutations. Using biochemical and electrophysiological techniques, we found that WT, but not mutated, MLC1 expression favors intercellular communication by inhibiting extracellular-signal-regulated kinase 1/2 (ERK1/2)-mediated Cx43 phosphorylation and increasing Cx43 gap-junction stability. These data indicate MLC1 regulation of Cx43 in astrocytes and Cx43 involvement in MLC pathogenesis, suggesting potential target pathways for therapeutic interventions.
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spelling pubmed-73487692020-07-20 Megalencephalic Leukoencephalopathy with Subcortical Cysts Disease-Linked MLC1 Protein Favors Gap-Junction Intercellular Communication by Regulating Connexin 43 Trafficking in Astrocytes Lanciotti, Angela Brignone, Maria Stefania Belfiore, Marcello Columba-Cabezas, Sandra Mallozzi, Cinzia Vincentini, Olimpia Molinari, Paola Petrucci, Tamara Corinna Visentin, Sergio Ambrosini, Elena Cells Article Astrocytes, the most numerous cells of the central nervous system, exert critical functions for brain homeostasis. To this purpose, astrocytes generate a highly interconnected intercellular network allowing rapid exchange of ions and metabolites through gap junctions, adjoined channels composed of hexamers of connexin (Cx) proteins, mainly Cx43. Functional alterations of Cxs and gap junctions have been observed in several neuroinflammatory/neurodegenerative diseases. In the rare leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts (MLC), astrocytes show defective control of ion/fluid exchanges causing brain edema, fluid cysts, and astrocyte/myelin vacuolation. MLC is caused by mutations in MLC1, an astrocyte-specific protein of elusive function, and in GlialCAM, a MLC1 chaperon. Both proteins are highly expressed at perivascular astrocyte end-feet and astrocyte-astrocyte contacts where they interact with zonula occludens-1 (ZO-1) and Cx43 junctional proteins. To investigate the possible role of Cx43 in MLC pathogenesis, we studied Cx43 properties in astrocytoma cells overexpressing wild type (WT) MLC1 or MLC1 carrying pathological mutations. Using biochemical and electrophysiological techniques, we found that WT, but not mutated, MLC1 expression favors intercellular communication by inhibiting extracellular-signal-regulated kinase 1/2 (ERK1/2)-mediated Cx43 phosphorylation and increasing Cx43 gap-junction stability. These data indicate MLC1 regulation of Cx43 in astrocytes and Cx43 involvement in MLC pathogenesis, suggesting potential target pathways for therapeutic interventions. MDPI 2020-06-08 /pmc/articles/PMC7348769/ /pubmed/32521795 http://dx.doi.org/10.3390/cells9061425 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lanciotti, Angela
Brignone, Maria Stefania
Belfiore, Marcello
Columba-Cabezas, Sandra
Mallozzi, Cinzia
Vincentini, Olimpia
Molinari, Paola
Petrucci, Tamara Corinna
Visentin, Sergio
Ambrosini, Elena
Megalencephalic Leukoencephalopathy with Subcortical Cysts Disease-Linked MLC1 Protein Favors Gap-Junction Intercellular Communication by Regulating Connexin 43 Trafficking in Astrocytes
title Megalencephalic Leukoencephalopathy with Subcortical Cysts Disease-Linked MLC1 Protein Favors Gap-Junction Intercellular Communication by Regulating Connexin 43 Trafficking in Astrocytes
title_full Megalencephalic Leukoencephalopathy with Subcortical Cysts Disease-Linked MLC1 Protein Favors Gap-Junction Intercellular Communication by Regulating Connexin 43 Trafficking in Astrocytes
title_fullStr Megalencephalic Leukoencephalopathy with Subcortical Cysts Disease-Linked MLC1 Protein Favors Gap-Junction Intercellular Communication by Regulating Connexin 43 Trafficking in Astrocytes
title_full_unstemmed Megalencephalic Leukoencephalopathy with Subcortical Cysts Disease-Linked MLC1 Protein Favors Gap-Junction Intercellular Communication by Regulating Connexin 43 Trafficking in Astrocytes
title_short Megalencephalic Leukoencephalopathy with Subcortical Cysts Disease-Linked MLC1 Protein Favors Gap-Junction Intercellular Communication by Regulating Connexin 43 Trafficking in Astrocytes
title_sort megalencephalic leukoencephalopathy with subcortical cysts disease-linked mlc1 protein favors gap-junction intercellular communication by regulating connexin 43 trafficking in astrocytes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348769/
https://www.ncbi.nlm.nih.gov/pubmed/32521795
http://dx.doi.org/10.3390/cells9061425
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