Topic
GRID2
About: GRID2 is a research topic. Over the lifetime, 39 publications have been published within this topic receiving 3041 citations. The topic is also known as: GluD2 & SCAR18.
Papers
TL;DR: The activation of apoptotic neuronal death in Lurcher mice may provide a physiologically relevant model for excitotoxic cell death, demonstrating that Lc is inherited as a neurodegenerative disorder resulting from a gain-of-function mutation in a glutamate receptor gene.
Abstract: Lurcher (Lc) is a spontaneous, semidominant mouse neurological mutation. Heterozygous Lurcher mice (Lc/+) display ataxia as a result of a selective, cell-autonomous and apoptotic death of cerebellar Purkinje cells during postnatal development. Homozygous Lurcher mice (Lc/Lc) die shortly after birth because of a massive loss of mid- and hindbrain neurons during late embryogenesis. We have used positional cloning to identify the mutations responsible for neurodegeneration in two independent Lc alleles as G-to-A transitions that change a highly conserved alanine to a threonine residue in transmembrane domain III of the mouse delta2 glutamate receptor gene (GluR delta2). Lc/+ Purkinje cells have a very high membrane conductance and a depolarized resting potential, indicating the presence of a large, constitutive inward current. Expression of the mutant GluR delta2(Lc) protein in Xenopus oocytes confirmed these results, demonstrating that Lc is inherited as a neurodegenerative disorder resulting from a gain-of-function mutation in a glutamate receptor gene. Thus the activation of apoptotic neuronal death in Lurcher mice may provide a physiologically relevant model for excitotoxic cell death.
568 citations
TL;DR: The rat delta‐2 gene is expressed predominantly in Purkinje cells of the cerebellum whereas only low levels of delta‐1 transcripts are found in the adult brain, with particularly high mRNA levels in the caudate putamen of late embryonic/early postnatal stages.
356 citations
University of Washington1, Central South University2, Karolinska Institutet3, University of Adelaide4, South Australia Pathology5, Boston Children's Hospital6, University of Antwerp7, University of California, San Diego8, University of Iowa9, Charles University in Prague10, Leiden University Medical Center11, Katholieke Universiteit Leuven12, University of Pennsylvania13, Howard Hughes Medical Institute14
TL;DR: Overall, significant clustering of de novo mutations in 200 genes is found, highlighting specific functional domains and synaptic candidate genes important in NDD pathology.
Abstract: Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,688 patients with NDD identified 21 new patients with identical missense mutations. One recurrent site substitution (p.A636T) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology.
164 citations
TL;DR: The authors' gene expression analyses revealed downregulation of several components of fragile X mental retardation protein (FMRP) targets in TSC2-deficient hiPSC-PCs, and these findings suggest that these gene expression changes and cellular abnormalities contribute to aberrant PC function during development in T SC affected individuals.
Abstract: Accumulating evidence suggests that cerebellar dysfunction early in life is associated with autism spectrum disorder (ASD), but the molecular mechanisms underlying the cerebellar deficits at the cellular level are unclear. Tuberous sclerosis complex (TSC) is a neurocutaneous disorder that often presents with ASD. Here, we developed a cerebellar Purkinje cell (PC) model of TSC with patient-derived human induced pluripotent stem cells (hiPSCs) to characterize the molecular mechanisms underlying cerebellar abnormalities in ASD and TSC. Our results show that hiPSC-derived PCs from patients with pathogenic TSC2 mutations displayed mTORC1 pathway hyperactivation, defects in neuronal differentiation and RNA regulation, hypoexcitability and reduced synaptic activity when compared with those derived from controls. Our gene expression analyses revealed downregulation of several components of fragile X mental retardation protein (FMRP) targets in TSC2-deficient hiPSC-PCs. We detected decreased expression of FMRP, glutamate receptor δ2 (GRID2), and pre- and post-synaptic markers such as synaptophysin and PSD95 in the TSC2-deficient hiPSC-PCs. The mTOR inhibitor rapamycin rescued the deficits in differentiation, synaptic dysfunction, and hypoexcitability of TSC2 mutant hiPSC-PCs in vitro. Our findings suggest that these gene expression changes and cellular abnormalities contribute to aberrant PC function during development in TSC affected individuals.
108 citations
TL;DR: Claims that the presence of naked spines not innervated by parallel fibers may influence the sustained innervation of mutant Purkinje cells by multiple climbing fibers and several hypotheses about mechanisms by which GluRδ2 functions are proposed are proposed.
107 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2021 | 1 |
| 2020 | 1 |
| 2019 | 1 |
| 2018 | 1 |
| 2017 | 3 |
| 2016 | 1 |