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Neuroligin 1, 2, and 3 Regulation at the Synapse: FMRP-Dependent Translation and Activity-Induced Proteolytic Cleavage

Neuroligins (NLGNs) are cell adhesion molecules located on the postsynaptic side of the synapse that interact with their presynaptic partners neurexins to maintain trans-synaptic connection. Fragile X syndrome (FXS) is a common neurodevelopmental disease that often co-occurs with autism and is cause...

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Autores principales: Chmielewska, Joanna J., Kuzniewska, Bozena, Milek, Jacek, Urbanska, Katarzyna, Dziembowska, Magdalena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459971/
https://www.ncbi.nlm.nih.gov/pubmed/30056576
http://dx.doi.org/10.1007/s12035-018-1243-1
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author Chmielewska, Joanna J.
Kuzniewska, Bozena
Milek, Jacek
Urbanska, Katarzyna
Dziembowska, Magdalena
author_facet Chmielewska, Joanna J.
Kuzniewska, Bozena
Milek, Jacek
Urbanska, Katarzyna
Dziembowska, Magdalena
author_sort Chmielewska, Joanna J.
collection PubMed
description Neuroligins (NLGNs) are cell adhesion molecules located on the postsynaptic side of the synapse that interact with their presynaptic partners neurexins to maintain trans-synaptic connection. Fragile X syndrome (FXS) is a common neurodevelopmental disease that often co-occurs with autism and is caused by the lack of fragile X mental retardation protein (FMRP) expression. To gain an insight into the molecular interactions between the autism-related genes, we sought to determine whether FMRP controls the synaptic levels of NLGNs. We show evidences that FMRP associates with Nlgn1, Nlgn2, and Nlgn3 mRNAs in vitro in both synaptoneurosomes and neuronal cultures. Next, we confirm local translation of Nlgn1, Nlgn2, and Nlgn3 mRNAs to be synaptically regulated by FMRP. As a consequence of elevated Nlgns mRNA translation Fmr1 KO mice exhibit increased incorporation of NLGN1 and NLGN3 into the postsynaptic membrane. Finally, we show that neuroligins synaptic level is precisely and dynamically regulated by their rapid proteolytic cleavage upon NMDA receptor stimulation in both wild type and Fmr1 KO mice. In aggregate, our study provides a novel approach to understand the molecular basis of FXS by linking the dysregulated synaptic expression of NLGNs with FMRP. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12035-018-1243-1) contains supplementary material, which is available to authorized users.
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spelling pubmed-64599712019-05-03 Neuroligin 1, 2, and 3 Regulation at the Synapse: FMRP-Dependent Translation and Activity-Induced Proteolytic Cleavage Chmielewska, Joanna J. Kuzniewska, Bozena Milek, Jacek Urbanska, Katarzyna Dziembowska, Magdalena Mol Neurobiol Article Neuroligins (NLGNs) are cell adhesion molecules located on the postsynaptic side of the synapse that interact with their presynaptic partners neurexins to maintain trans-synaptic connection. Fragile X syndrome (FXS) is a common neurodevelopmental disease that often co-occurs with autism and is caused by the lack of fragile X mental retardation protein (FMRP) expression. To gain an insight into the molecular interactions between the autism-related genes, we sought to determine whether FMRP controls the synaptic levels of NLGNs. We show evidences that FMRP associates with Nlgn1, Nlgn2, and Nlgn3 mRNAs in vitro in both synaptoneurosomes and neuronal cultures. Next, we confirm local translation of Nlgn1, Nlgn2, and Nlgn3 mRNAs to be synaptically regulated by FMRP. As a consequence of elevated Nlgns mRNA translation Fmr1 KO mice exhibit increased incorporation of NLGN1 and NLGN3 into the postsynaptic membrane. Finally, we show that neuroligins synaptic level is precisely and dynamically regulated by their rapid proteolytic cleavage upon NMDA receptor stimulation in both wild type and Fmr1 KO mice. In aggregate, our study provides a novel approach to understand the molecular basis of FXS by linking the dysregulated synaptic expression of NLGNs with FMRP. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12035-018-1243-1) contains supplementary material, which is available to authorized users. Springer US 2018-07-28 2019 /pmc/articles/PMC6459971/ /pubmed/30056576 http://dx.doi.org/10.1007/s12035-018-1243-1 Text en © The Author(s) 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Article
Chmielewska, Joanna J.
Kuzniewska, Bozena
Milek, Jacek
Urbanska, Katarzyna
Dziembowska, Magdalena
Neuroligin 1, 2, and 3 Regulation at the Synapse: FMRP-Dependent Translation and Activity-Induced Proteolytic Cleavage
title Neuroligin 1, 2, and 3 Regulation at the Synapse: FMRP-Dependent Translation and Activity-Induced Proteolytic Cleavage
title_full Neuroligin 1, 2, and 3 Regulation at the Synapse: FMRP-Dependent Translation and Activity-Induced Proteolytic Cleavage
title_fullStr Neuroligin 1, 2, and 3 Regulation at the Synapse: FMRP-Dependent Translation and Activity-Induced Proteolytic Cleavage
title_full_unstemmed Neuroligin 1, 2, and 3 Regulation at the Synapse: FMRP-Dependent Translation and Activity-Induced Proteolytic Cleavage
title_short Neuroligin 1, 2, and 3 Regulation at the Synapse: FMRP-Dependent Translation and Activity-Induced Proteolytic Cleavage
title_sort neuroligin 1, 2, and 3 regulation at the synapse: fmrp-dependent translation and activity-induced proteolytic cleavage
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459971/
https://www.ncbi.nlm.nih.gov/pubmed/30056576
http://dx.doi.org/10.1007/s12035-018-1243-1
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