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MECP2 Increases the Pro-Inflammatory Response of Microglial Cells and Phosphorylation at Serine 423 Regulates Neuronal Gene Expression upon Neuroinflammation

Methyl-CpG-binding protein 2 (MECP2) is a critical transcriptional regulator for synaptic function. Dysfunction of synapses, as well as microglia-mediated neuroinflammation, represent the earliest pathological events in Alzheimer’s disease (AD). Here, expression, protein levels, and activity-related...

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Autores principales: Wittrahm, Rebekka, Takalo, Mari, Marttinen, Mikael, Kuulasmaa, Teemu, Mäkinen, Petra, Kemppainen, Susanna, Martiskainen, Henna, Rauramaa, Tuomas, Pike, Ian, Leinonen, Ville, Natunen, Teemu, Haapasalo, Annakaisa, Hiltunen, Mikko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070522/
https://www.ncbi.nlm.nih.gov/pubmed/33918872
http://dx.doi.org/10.3390/cells10040860
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author Wittrahm, Rebekka
Takalo, Mari
Marttinen, Mikael
Kuulasmaa, Teemu
Mäkinen, Petra
Kemppainen, Susanna
Martiskainen, Henna
Rauramaa, Tuomas
Pike, Ian
Leinonen, Ville
Natunen, Teemu
Haapasalo, Annakaisa
Hiltunen, Mikko
author_facet Wittrahm, Rebekka
Takalo, Mari
Marttinen, Mikael
Kuulasmaa, Teemu
Mäkinen, Petra
Kemppainen, Susanna
Martiskainen, Henna
Rauramaa, Tuomas
Pike, Ian
Leinonen, Ville
Natunen, Teemu
Haapasalo, Annakaisa
Hiltunen, Mikko
author_sort Wittrahm, Rebekka
collection PubMed
description Methyl-CpG-binding protein 2 (MECP2) is a critical transcriptional regulator for synaptic function. Dysfunction of synapses, as well as microglia-mediated neuroinflammation, represent the earliest pathological events in Alzheimer’s disease (AD). Here, expression, protein levels, and activity-related phosphorylation changes of MECP2 were analyzed in post-mortem human temporal cortex. The effects of wild type and phosphorylation-deficient MECP2 variants at serine 423 (S423) or S80 on microglial and neuronal function were assessed utilizing BV2 microglial monocultures and co-cultures with mouse cortical neurons under inflammatory stress conditions. MECP2 phosphorylation at the functionally relevant S423 site nominally decreased in the early stages of AD-related neurofibrillary pathology in the human temporal cortex. Overexpression of wild type MECP2 enhanced the pro-inflammatory response in BV2 cells upon treatment with lipopolysaccharide (LPS) and interferon-γ (IFNγ) and decreased BV2 cell phagocytic activity. The expression of the phosphorylation-deficient MECP2-S423A variant, but not S80A, further increased the pro-inflammatory response of BV2 cells. In neurons co-cultured with BV2 cells, the MECP2-S423A variant increased the expression of several genes, which are important for the maintenance and protection of neurons and synapses upon inflammatory stress. Collectively, functional analyses in different cellular models suggest that MECP2 may influence the inflammatory response in microglia independently of S423 and S80 phosphorylation, while the S423 phosphorylation might play a role in the activation of neuronal gene expression, which conveys neuroprotection under neuroinflammation-related stress.
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spelling pubmed-80705222021-04-26 MECP2 Increases the Pro-Inflammatory Response of Microglial Cells and Phosphorylation at Serine 423 Regulates Neuronal Gene Expression upon Neuroinflammation Wittrahm, Rebekka Takalo, Mari Marttinen, Mikael Kuulasmaa, Teemu Mäkinen, Petra Kemppainen, Susanna Martiskainen, Henna Rauramaa, Tuomas Pike, Ian Leinonen, Ville Natunen, Teemu Haapasalo, Annakaisa Hiltunen, Mikko Cells Article Methyl-CpG-binding protein 2 (MECP2) is a critical transcriptional regulator for synaptic function. Dysfunction of synapses, as well as microglia-mediated neuroinflammation, represent the earliest pathological events in Alzheimer’s disease (AD). Here, expression, protein levels, and activity-related phosphorylation changes of MECP2 were analyzed in post-mortem human temporal cortex. The effects of wild type and phosphorylation-deficient MECP2 variants at serine 423 (S423) or S80 on microglial and neuronal function were assessed utilizing BV2 microglial monocultures and co-cultures with mouse cortical neurons under inflammatory stress conditions. MECP2 phosphorylation at the functionally relevant S423 site nominally decreased in the early stages of AD-related neurofibrillary pathology in the human temporal cortex. Overexpression of wild type MECP2 enhanced the pro-inflammatory response in BV2 cells upon treatment with lipopolysaccharide (LPS) and interferon-γ (IFNγ) and decreased BV2 cell phagocytic activity. The expression of the phosphorylation-deficient MECP2-S423A variant, but not S80A, further increased the pro-inflammatory response of BV2 cells. In neurons co-cultured with BV2 cells, the MECP2-S423A variant increased the expression of several genes, which are important for the maintenance and protection of neurons and synapses upon inflammatory stress. Collectively, functional analyses in different cellular models suggest that MECP2 may influence the inflammatory response in microglia independently of S423 and S80 phosphorylation, while the S423 phosphorylation might play a role in the activation of neuronal gene expression, which conveys neuroprotection under neuroinflammation-related stress. MDPI 2021-04-09 /pmc/articles/PMC8070522/ /pubmed/33918872 http://dx.doi.org/10.3390/cells10040860 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wittrahm, Rebekka
Takalo, Mari
Marttinen, Mikael
Kuulasmaa, Teemu
Mäkinen, Petra
Kemppainen, Susanna
Martiskainen, Henna
Rauramaa, Tuomas
Pike, Ian
Leinonen, Ville
Natunen, Teemu
Haapasalo, Annakaisa
Hiltunen, Mikko
MECP2 Increases the Pro-Inflammatory Response of Microglial Cells and Phosphorylation at Serine 423 Regulates Neuronal Gene Expression upon Neuroinflammation
title MECP2 Increases the Pro-Inflammatory Response of Microglial Cells and Phosphorylation at Serine 423 Regulates Neuronal Gene Expression upon Neuroinflammation
title_full MECP2 Increases the Pro-Inflammatory Response of Microglial Cells and Phosphorylation at Serine 423 Regulates Neuronal Gene Expression upon Neuroinflammation
title_fullStr MECP2 Increases the Pro-Inflammatory Response of Microglial Cells and Phosphorylation at Serine 423 Regulates Neuronal Gene Expression upon Neuroinflammation
title_full_unstemmed MECP2 Increases the Pro-Inflammatory Response of Microglial Cells and Phosphorylation at Serine 423 Regulates Neuronal Gene Expression upon Neuroinflammation
title_short MECP2 Increases the Pro-Inflammatory Response of Microglial Cells and Phosphorylation at Serine 423 Regulates Neuronal Gene Expression upon Neuroinflammation
title_sort mecp2 increases the pro-inflammatory response of microglial cells and phosphorylation at serine 423 regulates neuronal gene expression upon neuroinflammation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070522/
https://www.ncbi.nlm.nih.gov/pubmed/33918872
http://dx.doi.org/10.3390/cells10040860
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