Genomic evidence for the suitability of Göttingen Minipigs with a rare seizure phenotype as a model for human epilepsy DOI Creative Commons
Pardis Najafi, Christian Reimer, Jonathan D. Gilthorpe

et al.

Neurogenetics, Journal Year: 2024, Volume and Issue: 25(2), P. 103 - 117

Published: Feb. 21, 2024

Abstract Epilepsy is a complex genetic disorder that affects about 2% of the global population. Although frequency and severity epileptic seizures can be reduced by range pharmacological interventions, there are no disease-modifying treatments for epilepsy. The development new more effective drugs hindered lack suitable animal models. Available rodent models may not recapitulate all key aspects disease. Spontaneous convulsions were observed in few Göttingen Minipigs (GMPs), which provide valuable alternative model characterisation epilepsy-type diseases testing treatments. We have characterised affected GMPs at genome level taken advantage primary fibroblast cultures to validate functional impact fixed variants on transcriptome level. found numerous genes connected calcium metabolism been associated with epilepsy before, such as ADORA2B , CAMK1D ITPKB MCOLN2 MYLK NFATC3 PDGFD PHKB . Our results identified two transcription factor genes, EGR3 HOXB6 potential regulators CACNA1H was previously linked disorders humans. findings first set conclusive support use subsets an reliable system study human Further neurological validation suitability therefore warranted.

Language: Английский

Key Roles of CACNA1C/Cav1.2 and CALB1/Calbindin in Prefrontal Neurons Altered in Cognitive Disorders DOI Creative Commons
Dibyadeep Datta, Shengtao Yang, Mary Kate P. Joyce

et al.

JAMA Psychiatry, Journal Year: 2024, Volume and Issue: 81(9), P. 870 - 870

Published: May 22, 2024

Importance The risk of mental disorders is consistently associated with variants in CACNA1C (L-type calcium channel Cav1.2) but it not known why these channels are critical to cognition, and whether they affect the layer III pyramidal cells dorsolateral prefrontal cortex that especially vulnerable cognitive disorders. Objective To examine molecular mechanisms expressed primate cortices. Design, Setting, Participants design included transcriptomic analyses from human macaque cortex, connectivity, protein expression, physiology, behavior macaques. research was performed academic laboratories at Yale, Harvard, Princeton, University Pittsburgh. As only exists primates, work evaluated humans Main Outcomes Measures Outcome measures signatures cells, expression interactions using light electron microscopy, changes neuronal firing during spatial working memory, memory performance following pharmacological treatments. Results Layer coexpress a constellation calcium-related proteins, delineated by CALB1 (calbindin), high levels (Cav1.2), GRIN2B (NMDA receptor GluN2B), KCNN3 (SK3 potassium channel), concentrated dendritic spines near calcium-storing smooth endoplasmic reticulum. L-type influenced needed for where either blockade or increased drive β1-adrenoceptors, reduced mean (SD) 37.3% (5.5%) 40% (6.3%), respectively, latter via SK opening. An blocker β1-adrenoceptor antagonist protected stress. Conclusions Relevance differentially express calbindin proteins including Cav1.2 ( ), GluN2B-NMDA receptors SK3 which influence memory-related firing. finding inadequate excessive activation explains loss- gain-of-function were selective highlights importance regulatory neurons signaling, consistent Alzheimer tau pathology emerging when lost age and/or inflammation.

Language: Английский

Citations

13
MiRNA-223-5p inhibits hypoxia-induced apoptosis of BMSCs and promotes repair in Legg-Calvé-Perthes disease by targeting CHAC2 and activating the Wnt/β-catenin signaling pathway DOI Creative Commons
Jiafei Yang,

Tianjiu Zhang,

Xingtao Zhu

et al.

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(1), P. e0315230 - e0315230

Published: Jan. 24, 2025

Legg-Calvé-Perthes disease (LCPD) involves femoral head osteonecrosis caused by disrupted blood supply, leading to joint deformity and early osteoarthritis. This study investigates the role of miRNA-223-5p in regulating hypoxia-induced apoptosis enhancing osteogenesis bone marrow mesenchymal stem cells (BMSCs). Utilizing a juvenile New Zealand white rabbit model LCPD established through neck ligation, we transfected BMSCs with miR-223-5p mimics, inhibitors, controls, followed hypoxic exposure. The impact on BMSC was assessed using qPCR, Western blotting, dual-luciferase reporter assays, focusing Wnt/β-catenin signaling pathway. In vivo, evaluated effects transplanting miR-223-5p-overexpressing into model. Our results indicate that is downregulated under conditions. Overexpression inhibited activated pathway directly targeting CHAC2. enhanced reduced necrosis These findings suggest inhibits CHAC2 activating pathway, proposing as promising target for improving repair ischemic

Language: Английский

Citations

1
Requirements for the neurodevelopmental disorder-associated gene ZNF292 in human cortical interneuron development and function DOI
Komal Kaushik, Gareth Chapman, Ramachandran Prakasam

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(5), P. 115597 - 115597

Published: April 20, 2025

Language: Английский

Citations

1
NMDA receptor-mediated Ca2+ signaling: Impact on cell cycle regulation and the development of neurodegenerative diseases and cancer DOI
Ana Laura González‐Cota, Daniel Martínez-Flores, Margarita Jacaranda Rosendo‐Pineda

et al.

Cell Calcium, Journal Year: 2024, Volume and Issue: 119, P. 102856 - 102856

Published: Feb. 14, 2024

Language: Английский

Citations

9
Anterior cingulate cortex-related functional hyperconnectivity underlies sensory hypersensitivity in Grin2b-mutant mice DOI Creative Commons
Soowon Lee, Won Beom Jung,

Heera Moon

et al.

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(10), P. 3195 - 3207

Published: May 4, 2024

Sensory abnormalities are observed in ~90% of individuals with autism spectrum disorders (ASD), but the underlying mechanisms poorly understood. GluN2B, an NMDA receptor subunit that regulates long-term depression and circuit refinement during brain development, has been strongly implicated ASD, whether GRIN2B mutations lead to sensory remains unclear. Here, we report Grin2b-mutant mice show behavioral hypersensitivity hyperconnectivity associated anterior cingulate cortex (ACC). a patient-derived C456Y mutation (Grin2b

Language: Английский

Citations

6
Disease-Associated Variants in GRIN1, GRIN2A and GRIN2B genes: Insights into NMDA Receptor Structure, Function, and Pathophysiology DOI Creative Commons
Michal Korinek,

M C Serra,

Fes Abdel Rahman

et al.

Physiological Research, Journal Year: 2024, Volume and Issue: Suppl 1, P. S413 - S434

Published: Aug. 22, 2024

N-methyl-D-aspartate receptors (NMDARs) are a subtype of ionotropic glutamate critical for synaptic transmission and plasticity, the development neural circuits. Rare or de-novo variants in GRIN genes encoding NMDAR subunits have been associated with neurodevelopmental disorders characterized by intellectual disability, developmental delay, autism, schizophrenia, epilepsy. In recent years, some disease-associated using recombinant expressed non-neuronal cells, few also studied neuronal preparations animal models. Here we review current literature on functional evaluation human GRIN1, GRIN2A GRIN2B at all levels analysis. Focusing impact different patient level receptor function, discuss effects agonist co-agonist affinity, channel open probability, cell surface expression. We consider how such receptor-level information may be used to classify as gain-of-function loss-of-function, limitations this classification synaptic, cellular, system level. Together work many laboratories worldwide yields valuable insights into structure represents significant progress effort understand treat disorders. Keywords: NMDA , genes, Genetic variants, Electrophysiology, Synapse, Animal

Language: Английский

Citations

6
Quantitative proteomics of dorsolateral prefrontal cortex reveals an early pattern of synaptic dysmaturation in children with idiopathic autism DOI
S. Hossein Fatemi, Arthur C. Eschenlauer,

Justin W. Aman

et al.

Cerebral Cortex, Journal Year: 2024, Volume and Issue: 34(13), P. 161 - 171

Published: May 1, 2024

Autism spectrum disorder (ASD) is a developmental with rising prevalence and unknown etiology presenting deficits in cognition abnormal behavior. We hypothesized that the investigation of synaptic component prefrontal cortex may provide proteomic signatures identify biological underpinnings cognitive childhood ASD. Subcellular fractions synaptosomes from cortices age-, brain area-, postmortem-interval-matched samples children adults idiopathic ASD vs. controls were subjected to HPLC-tandem mass spectrometry. Analysis data revealed enrichment risk genes participate slow maturation postsynaptic density (PSD) structure function during early development. Proteomic analysis down regulation PSD-related proteins including AMPA NMDA receptors, GRM3, DLG4, olfactomedins, Shank1-3, Homer1, CaMK2α, NRXN1, NLGN2, Drebrin1, ARHGAP32, Dock9 autism (FDR-adjusted P < 0.05). In contrast, alterations less severe or unchanged adult individuals Network analyses glutamate receptor abnormalities. Overall, support concept synaptopathy involving genes. Interruption evolutionarily conserved PSD complex lead development susceptible individual.

Language: Английский

Citations

4
Structural and biochemical alterations in dendritic spines as key mechanisms for severe mental illnesses DOI

Sebastian Reyes-Lizaola,

Ulises Luna-Zarate, Hiram Tendilla‐Beltrán

et al.

Progress in Neuro-Psychopharmacology and Biological Psychiatry, Journal Year: 2023, Volume and Issue: 129, P. 110876 - 110876

Published: Oct. 19, 2023

Language: Английский

Citations

10
Integrative multiomics reveals common endotypes across PSEN1, PSEN2, and APP mutations in familial Alzheimer’s disease DOI Creative Commons
Phoebe Valdes, Andrew B. Caldwell, Qing Liu

et al.

Alzheimer s Research & Therapy, Journal Year: 2025, Volume and Issue: 17(1)

Published: Jan. 4, 2025

Abstract Background PSEN1, PSEN2, and APP mutations cause Alzheimer’s disease (AD) with an early age at onset (AAO) progressive cognitive decline. PSEN1 are more common generally have earlier AAO; however, certain a later AAO, similar to those observed in PSEN2 . Methods We examined whether endotypes exist across these AAO (~ 55 years) using hiPSC-derived neurons from familial (FAD) patients harboring A79V , N141I V717I mechanistically characterized by integrating RNA-seq ATAC-seq. Results identified endotypes, such as dedifferentiation, dysregulation of synaptic signaling, repression mitochondrial function metabolism, inflammation. ascertained the master transcriptional regulators associated including REST, ASCL1, ZIC family members (activation), NRF1 (repression). Conclusions FAD share regulatory changes within varying severity, resulting reversion less-differentiated state. The mechanisms described offer potential targets for therapeutic interventions.

Language: Английский

Citations

0
Novel De Novo Intronic Variant of SYNGAP1 Associated With the Neurodevelopmental Disorders DOI Creative Commons

Wuming Xie,

Baoqiong Liao,

Mei Shuai

et al.

Molecular Genetics & Genomic Medicine, Journal Year: 2025, Volume and Issue: 13(2)

Published: Jan. 29, 2025

ABSTRACT Background SYNGAP1 encodes a Ras/Rap GTPase‐activating protein that is predominantly expressed in the brain with functional roles regulating synaptic plasticity, spine morphogenesis, and cognition function. Pathogenic variants have been associated spectrum of neurodevelopmental disorders characterized by developmental delays, intellectual disabilities, epilepsy, hypotonia, features autism disorder. The aim this study was to identify novel gene variant linked evaluate pathogenicity detected variant. Methods A de novo intronic identified Whole exome sequencing (WES) confirmed Sanger sequencing. Minigene assays were conducted assess whether influenced normal splicing mRNA. Results (c.3582+2T>G) indentified clinical suggestive related disorders. analysis demonstrated noncanonical splice site led activation cryptic acceptor site. Consequently, 101 base pairs intron 16 aberrantly retained mRNA, leading frameshift. This frameshift resulted introduction premature stop codon (TGA) coding sequence production truncated protein, potentially leding loss function subsequent disruption its biological roles. Conclusion Our findings highlight significance pathogenic at 16/exon 17 junction ‐related disorders, providing insights into genetic basis diagnosis these disabilities.

Language: Английский

Citations

0