Potential involvement of GRIN2B encoding the NMDA receptor subunit NR2B in the spectrum of Alzheimer’s disease

Andreoli, Virginia; Marco, Elvira Valeria De; Trecroci, Francesca; Cittadella, Rita; Palma, Gemma Di; Gambardella, Antonio

doi:10.1007/s00702-013-1125-7

Cited by 31 publications

(28 citation statements)

References 43 publications

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“…Human gene GRIN2B was mainly expressed in the central nervous system (CNS) which encodes the glutamate ionotropic receptor N-methyl-D-aspartate (NMDA) type subunit 2B [50] . As the agonist binding site for glutamate, GRIN2B acts as the major excitatory neurotransmitter receptor in the mammalian brain and variants of GRIN2B play roles in neurodegenerative diseases including AD, PD and HD [50][51][52].…”

Section: Discussionmentioning

confidence: 99%

The Differentially Expressed Circular RNAs in the Substantia Nigra and Corpus Striatum of Nrf2-Knockout Mice

Yang¹,

Zhang²,

Lin³

et al. 2018

Cell Physiol Biochem

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Background/Aims: The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway plays a protective role in both acute neuronal damage and chronic neurodegeneration-related oxidative stress. Circular RNAs (circRNAs) are involved with various diseases in the central nervous system (CNS). This study aimed to identify the key circRNAs involved in Nrf2-neuroprotection against oxidative stress. Methods: The differentially expressed circRNAs (DEcircRNAs) in the substantia nigra and corpus striatum between Nrf2 (-/-) and Nrf2 (+/+) mice were identified by microarray analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) was then used to validate the expression of selected DEcircRNAs in the substantia nigra and corpus striatum between Nrf2 (-/-) and Nrf2 (+/+) mice. Based on our previous microarray analysis of the differentially expressed mRNAs (DEmRNAs) in the substantia nigra and corpus striatum between Nrf2 (-/-) and Nrf2 (+/+) mice, the DEcircRNA-miRNA-DEmRNA interaction network was constructed. Functional annotation of DEmRNAs that shared the same binding miRNAs with DEcircRNAs was performed using gene ontology (GO) and pathway analyses. Results: A total of 65 and 150 significant DEcircRNAs were obtained in the substantia nigra and corpus striatum of Nrf2 (-/-) mice, respectively, and seventeen shared DEcircRNAs were found in both these two tissues. The qRT-PCR results were generally consistent with the microarray results. The DEcircRNA-miRNA-DEmRNA interaction network and pathway analysis indicated that mmu_circRNA_34132, mmu_circRNA_017077 and mmu-circRNA-015216 might be involved with Nrf2-mediated neuroprotection against oxidative stress. Mmu_circRNA_015216 and mmu_circRNA_017077 might play roles in the Nrf2-related transcriptional misregulation and Nrf2-mediated processes of rheumatoid arthritis, respectively. In addition to these two processes, mmu_circRNA_34132 may be a potential regulator of Nrf2-mediated protection for diabetes mellitus and Nrf2-mediated defence against ROS in hearts. Conclusion: In conclusion, our study identified the key DEcircRNAs in the substantia nigra and corpus striatum of Nrf2 (-/-) mice, which might provide new clues for further exploring the mechanism of Nrf2-mediated neuroprotection against oxidative stress and other Nrf2-mediated processes.

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Section: Discussionmentioning

confidence: 99%

The Differentially Expressed Circular RNAs in the Substantia Nigra and Corpus Striatum of Nrf2-Knockout Mice

Yang¹,

Zhang²,

Lin³

et al. 2018

Cell Physiol Biochem

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“…Whole-exome sequencing has also produced an enormous amount of data linking genetic composition to disease phenotype. Missense mutations located both in extracellular domains and transmembrane elements have been identified in patient cohorts with developmental disability or delays, epileptic encephalopathy, autism spectrum disorders (ASDs), and Alzheimer's disease (Endele et al, 2010;Tarabeux et al, 2011;de Ligt et al, 2012;Lemke et al, 2013;Lesca et al, 2013;Andreoli et al, 2014;Lemke et al, 2014;Fromer et al, 2014;Zhu et al, 2015;Swanger et al, 2016;for review, see Yuan et al, 2015 and. Although there are a growing number of variants being identified in patients with neurological disease, functional data exist for Ͻ10% of the rare variants and de novo mutations reported for the GRIN family of genes.…”

Section: Discussionmentioning

confidence: 99%

“…Conditional deletion of GluN2B at the bed nucleus of the stria terminalis eliminates LTP and actions of ethanol on NMDAR function (Wills et al, 2012). In addition to null mutations, there are multiple studies reporting GluN2B missense variants in patients with schizophrenia, autism, epilepsy, mental retardation, and other neurological or psychiatric diseases (Ohtsuki et al, 2001;Arning et al, 2007;Allen et al, 2008;Freunscht et al, 2013;Epi et al, 2013;Lemke et al, 2014;Hamdan et al, 2014;Andreoli et al, 2014;Zhu et al, 2015;Swanger et al, 2016;for review, see Yuan et al, 2015 and. However, pathological and biological consequences of these missense variants have not been well-characterized in humans or animal models.…”

Section: Introductionmentioning

confidence: 99%

A Rare Variant Identified Within the GluN2B C-Terminus in a Patient with Autism Affects NMDA Receptor Surface Expression and Spine Density

Liu¹,

Zhou

Yuan

et al. 2017

J. Neurosci.

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NMDA receptors (NMDARs) are ionotropic glutamate receptors that are crucial for neuronal development and higher cognitive processes. NMDAR dysfunction is involved in a variety of neurological and psychiatric diseases; however, the mechanistic link between the human pathology and NMDAR dysfunction is poorly understood. Rare missense variants within NMDAR subunits have been identified in numerous patients with mental or neurological disorders. We specifically focused on the GluN2B NMDAR subunit, which is highly expressed in the hippocampus and cortex throughout development. We analyzed several variants located in the GluN2B C terminus and found that three variants in patients with autism (S1415L) or schizophrenia (L1424F and S1452F) (S1413L, L1422F, and S1450F in rodents, respectively) displayed impaired binding to membrane-associated guanylate kinase (MAGUK) proteins. In addition, we observed a deficit in surface expression for GluN2B S1413L. Furthermore, there were fewer dendritic spines in GluN2B S1413L-expressing neurons. Importantly, synaptic NMDAR currents in neurons transfected with GluN2B S1413L in GluN2A/B-deficient mouse brain slices revealed only partial rescue of synaptic current amplitude. Functional properties of GluN2B S1413L in recombinant systems revealed no change in receptor properties, consistent with synaptic defects being the result of reduced trafficking and targeting of GluN2B S1413L to the synapse. Therefore, we find that GluN2B S1413L displays deficits in NMDAR trafficking, synaptic currents, and spine density, raising the possibility that this mutation may contribute to the phenotype in this autism patient. More broadly, our research demonstrates that the targeted study of certain residues in NMDARs based on rare variants identified in patients is a powerful approach to studying receptor function.

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“…The profound increase in the current produced by this mutation seems likely to drive aberrant excitation and potentially contribute to neuronal loss and consequently the patients' clinical symptoms. In subsequent years, a large number of missense mutations and deletions/truncations (.100) have been identified through whole exome and genome sequencing (reviewed by Soto et al, 2014;Burnashev and Szepetowski, 2015) and are scattered across all domains in NMDA receptor subunits (Supplemental Table S2; Tables 2 and 3) Myers et al, 2011;Tarabeux et al, 2011;de Ligt et al, 2012;O'Roak et al, 2012;Carvill et al, 2013b, DeVries andPatel, 2013;Epi4K and Epilepsy Phenome/ Genome Project, 2013;Freunscht et al, 2013;Lemke et al, 2013Lemke et al, , 2014Lesca et al, 2013;Adams et al, 2014;Andreoli et al, 2014;Fromer et al, 2014;Kenny et al, 2014;Pierson et al, 2014;Redin et al, 2014;Venkateswaran et al, 2014;Yuan et al, 2014;Burnashev and Szepetowski, 2015;Ohba et al, 2015;Turner et al, 2015). More recently, several case-control studies have isolated de novo and inherited mutations in the GRIN2A gene in patients diagnosed with different forms of epilepsy, including continuous spike-and-waves during slow-wave sleep syndrome, epileptic encephalopathy, Landau-Kleffner syndrome, and Rolandic epilepsy (Endele et al, 2010;Carvill et al, 2013b;Lemke et al, 2013;Lesca et al, 2013; reviewed by Burnashev and Szepetowski, 2015).…”

Section: Gaba/glutamate Receptor Mutations In Neurologic Diseasesmentioning

confidence: 99%

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

Yuan¹,

Low²,

Moody³

et al. 2015

Mol Pharmacol

182

176

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The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of diagnostic-targeted sequencing chips have resulted in an unprecedented volume of data directly linking patient genomic variability to disorders of the brain. This information has the potential to transform our understanding of neurologic disorders by improving diagnoses, illuminating the molecular heterogeneity underlying diseases, and identifying new targets for therapeutic treatment. There is a strong history of mutations in GABA receptor genes being involved in neurologic diseases, particularly the epilepsies. In addition, a substantial number of variants and mutations have been found in GABA receptor genes in patients with autism, schizophrenia, and addiction, suggesting potential links between the GABA receptors and these conditions. A new and unexpected outcome from sequencing efforts has been the surprising number of mutations found in glutamate receptor subunits, with the GRIN2A gene encoding the GluN2A N-methyl-D-aspartate receptor subunit being most often affected. These mutations are associated with multiple neurologic conditions, for which seizure disorders comprise the largest group. The GluN2A subunit appears to be a locus for epilepsy, which holds important therapeutic implications. Virtually all a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor mutations, most of which occur within GRIA3, are from patients with intellectual disabilities, suggesting a link to this condition. Similarly, the most common phenotype for kainate receptor variants is intellectual disability. Herein, we summarize the current understanding of disease-associated mutations in ionotropic GABA and glutamate receptor families, and discuss implications regarding the identification of human mutations and treatment of neurologic diseases.

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Potential involvement of GRIN2B encoding the NMDA receptor subunit NR2B in the spectrum of Alzheimer’s disease

Cited by 31 publications

References 43 publications

The Differentially Expressed Circular RNAs in the Substantia Nigra and Corpus Striatum of Nrf2-Knockout Mice

The Differentially Expressed Circular RNAs in the Substantia Nigra and Corpus Striatum of Nrf2-Knockout Mice

A Rare Variant Identified Within the GluN2B C-Terminus in a Patient with Autism Affects NMDA Receptor Surface Expression and Spine Density

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

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