TY - JOUR
T1 - An intellectual-disability-associated mutation of the transcriptional regulator NACC1 impairs glutamatergic neurotransmission
AU - Daniel, James A.
AU - Elizarova, Sofia
AU - Shaib, Ali H.
AU - Chouaib, Abed A.
AU - Magnussen, Helge M.
AU - Wang, Jianlong
AU - Brose, Nils
AU - Rhee, Jeong Seop
AU - Tirard, Marilyn
N1 - This work was supported by the German Research Foundation (SFB1286/A9, MT and NB). They would also like to acknowledge that their molecular graphics and analyses were performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from National Institutes of Health R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases.
Copyright:
© 2023 Daniel, Elizarova, Shaib, Chouaib, Magnussen, Wang, Brose, Rhee and Tirard.
PY - 2023/7/14
Y1 - 2023/7/14
N2 - 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.
AB - 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.
KW - NAC1/BTBD14B
KW - neuron
KW - SUMO
KW - synapse
KW - SynGAP1
UR - http://www.scopus.com/inward/record.url?scp=85166422002&partnerID=8YFLogxK
U2 - 10.3389/fnmol.2023.1115880
DO - 10.3389/fnmol.2023.1115880
M3 - Article
C2 - 37533751
AN - SCOPUS:85166422002
SN - 1662-5099
VL - 16
JO - Frontiers in Molecular Neuroscience
JF - Frontiers in Molecular Neuroscience
M1 - 1115880
ER -