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An intellectual-disability-associated mutation of the transcriptional regulator NACC1 impairs glutamatergic neurotransmission

Advances in genome sequencing technologies have favored the identification of rare de novo mutations linked to neurological disorders in humans. Recently, a de novo autosomal dominant mutation in NACC1 was identified (NM_052876.3: c.892C > T, NP_443108.1; p.Arg298Trp), associated with severe neur...

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Autores principales: Daniel, James A., Elizarova, Sofia, Shaib, Ali H., Chouaib, Abed A., Magnussen, Helge M., Wang, Jianlong, Brose, Nils, Rhee, JeongSeop, Tirard, Marilyn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10393139/
https://www.ncbi.nlm.nih.gov/pubmed/37533751
http://dx.doi.org/10.3389/fnmol.2023.1115880
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author Daniel, James A.
Elizarova, Sofia
Shaib, Ali H.
Chouaib, Abed A.
Magnussen, Helge M.
Wang, Jianlong
Brose, Nils
Rhee, JeongSeop
Tirard, Marilyn
author_facet Daniel, James A.
Elizarova, Sofia
Shaib, Ali H.
Chouaib, Abed A.
Magnussen, Helge M.
Wang, Jianlong
Brose, Nils
Rhee, JeongSeop
Tirard, Marilyn
author_sort Daniel, James A.
collection PubMed
description Advances in genome sequencing technologies have favored the identification of rare de novo mutations linked to neurological disorders in humans. Recently, a de novo autosomal dominant mutation in NACC1 was identified (NM_052876.3: c.892C > T, NP_443108.1; p.Arg298Trp), associated with severe neurological symptoms including intellectual disability, microcephaly, and epilepsy. As NACC1 had never before been associated with neurological diseases, we investigated how this mutation might lead to altered brain function. We examined neurotransmission in autaptic glutamatergic mouse neurons expressing the murine homolog of the human mutant NACC1, i.e., Nacc1-R284W. We observed that expression of Nacc1-R284W impaired glutamatergic neurotransmission in a cell-autonomous manner, likely through a dominant negative mechanism. Furthermore, by screening for Nacc1 interaction targets in the brain, we identified SynGAP1, GluK2A, and several SUMO E3 ligases as novel Nacc1 interaction partners. At a biochemical level, Nacc1-R284W exhibited reduced binding to SynGAP1 and GluK2A, and also showed greatly increased SUMOylation. Ablating the SUMOylation of Nacc1-R284W partially restored its interaction with SynGAP1 but did not restore binding to GluK2A. Overall, these data indicate a role for Nacc1 in regulating glutamatergic neurotransmission, which is substantially impaired by the expression of a disease-associated Nacc1 mutant. This study provides the first functional insights into potential deficits in neuronal function in patients expressing the de novo mutant NACC1 protein.
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spelling pubmed-103931392023-08-02 An intellectual-disability-associated mutation of the transcriptional regulator NACC1 impairs glutamatergic neurotransmission Daniel, James A. Elizarova, Sofia Shaib, Ali H. Chouaib, Abed A. Magnussen, Helge M. Wang, Jianlong Brose, Nils Rhee, JeongSeop Tirard, Marilyn Front Mol Neurosci Molecular Neuroscience Advances in genome sequencing technologies have favored the identification of rare de novo mutations linked to neurological disorders in humans. Recently, a de novo autosomal dominant mutation in NACC1 was identified (NM_052876.3: c.892C > T, NP_443108.1; p.Arg298Trp), associated with severe neurological symptoms including intellectual disability, microcephaly, and epilepsy. As NACC1 had never before been associated with neurological diseases, we investigated how this mutation might lead to altered brain function. We examined neurotransmission in autaptic glutamatergic mouse neurons expressing the murine homolog of the human mutant NACC1, i.e., Nacc1-R284W. We observed that expression of Nacc1-R284W impaired glutamatergic neurotransmission in a cell-autonomous manner, likely through a dominant negative mechanism. Furthermore, by screening for Nacc1 interaction targets in the brain, we identified SynGAP1, GluK2A, and several SUMO E3 ligases as novel Nacc1 interaction partners. At a biochemical level, Nacc1-R284W exhibited reduced binding to SynGAP1 and GluK2A, and also showed greatly increased SUMOylation. Ablating the SUMOylation of Nacc1-R284W partially restored its interaction with SynGAP1 but did not restore binding to GluK2A. Overall, these data indicate a role for Nacc1 in regulating glutamatergic neurotransmission, which is substantially impaired by the expression of a disease-associated Nacc1 mutant. This study provides the first functional insights into potential deficits in neuronal function in patients expressing the de novo mutant NACC1 protein. Frontiers Media S.A. 2023-07-14 /pmc/articles/PMC10393139/ /pubmed/37533751 http://dx.doi.org/10.3389/fnmol.2023.1115880 Text en Copyright © 2023 Daniel, Elizarova, Shaib, Chouaib, Magnussen, Wang, Brose, Rhee and Tirard. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Neuroscience
Daniel, James A.
Elizarova, Sofia
Shaib, Ali H.
Chouaib, Abed A.
Magnussen, Helge M.
Wang, Jianlong
Brose, Nils
Rhee, JeongSeop
Tirard, Marilyn
An intellectual-disability-associated mutation of the transcriptional regulator NACC1 impairs glutamatergic neurotransmission
title An intellectual-disability-associated mutation of the transcriptional regulator NACC1 impairs glutamatergic neurotransmission
title_full An intellectual-disability-associated mutation of the transcriptional regulator NACC1 impairs glutamatergic neurotransmission
title_fullStr An intellectual-disability-associated mutation of the transcriptional regulator NACC1 impairs glutamatergic neurotransmission
title_full_unstemmed An intellectual-disability-associated mutation of the transcriptional regulator NACC1 impairs glutamatergic neurotransmission
title_short An intellectual-disability-associated mutation of the transcriptional regulator NACC1 impairs glutamatergic neurotransmission
title_sort intellectual-disability-associated mutation of the transcriptional regulator nacc1 impairs glutamatergic neurotransmission
topic Molecular Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10393139/
https://www.ncbi.nlm.nih.gov/pubmed/37533751
http://dx.doi.org/10.3389/fnmol.2023.1115880
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