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1.
Front Cell Neurosci ; 17: 1146278, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37545878

RESUMO

Inhibitory γ-aminobutyric acid (GABA)-ergic interneurons mediate inhibition in neuronal circuitry and support normal brain function. Consequently, dysregulation of inhibition is implicated in various brain disorders. Parvalbumin (PV) and somatostatin (SST) interneurons, the two major types of GABAergic inhibitory interneurons in the hippocampus, exhibit distinct morpho-physiological properties and coordinate information processing and memory formation. However, the molecular mechanisms underlying the specialized properties of PV and SST interneurons remain unclear. This study aimed to compare the transcriptomic differences between these two classes of interneurons in the hippocampus using the ribosome tagging approach. The results revealed distinct expressions of genes such as voltage-gated ion channels and GABAA receptor subunits between PV and SST interneurons. Gabrd and Gabra6 were identified as contributors to the contrasting tonic GABAergic inhibition observed in PV and SST interneurons. Moreover, some of the differentially expressed genes were associated with schizophrenia and epilepsy. In conclusion, our results provide molecular insights into the distinct roles of PV and SST interneurons in health and disease.

2.
Genes (Basel) ; 12(10)2021 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-34680902

RESUMO

Major depressive disorder (MDD) is one of the most prevalent and disabling mental disorders worldwide. Among the symptoms of MDD, sleep disturbance such as insomnia is prominent, and the first reason patients may seek professional help. However, the underlying pathophysiology of this comorbidity is still elusive. Recently, genome-wide association studies (GWAS) have begun to unveil the genetic background of several psychiatric disorders, including MDD and insomnia. Identifying the shared genomic risk loci between comorbid psychiatric disorders could be a valuable strategy to understanding their comorbidity. This study seeks to identify the shared genes and biological pathways between MDD and insomnia based on their shared genetic variants. First, we performed a meta-analysis based on the GWAS summary statistics of MDD and insomnia obtained from Psychiatric Genomics Consortium and UK Biobank, respectively. Next, we associated shared genetic variants to genes using two gene mapping strategies: (a) positional mapping based on genomic proximity and (b) expression quantitative trait loci (eQTL) mapping based on gene expression linkage across multiple tissues. As a result, a total of 719 shared genes were identified. Over half (51%) of them are protein-coding genes. Functional enrichment analysis shows that the most enriched biological pathways are related to epigenetic modification, sensory perception, and immunologic signatures. We also identified druggable targets using a network approach. Together, these results may provide insights into understanding the genetic predisposition and underlying biological pathways of comorbid MDD and insomnia symptoms.


Assuntos
Transtorno Depressivo Maior/genética , Locos de Características Quantitativas , Distúrbios do Início e da Manutenção do Sono/genética , Transtorno Depressivo Maior/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Redes e Vias Metabólicas , Distúrbios do Início e da Manutenção do Sono/metabolismo
3.
Int J Mol Sci ; 22(1)2020 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-33396303

RESUMO

Endoplasmic reticulum (ER) stress response is an adaptive program to cope with cellular stress that disturbs the function and homeostasis of ER, which commonly occurs during cancer progression to late stage. Late-stage cancers, mostly requiring chemotherapy, often develop treatment resistance. Chemoresistance has been linked to ER stress response; however, most of the evidence has come from studies that correlate the expression of stress markers with poor prognosis or demonstrate proapoptosis by the knockdown of stress-responsive genes. Since ER stress in cancers usually persists and is essentially not induced by genetic manipulations, we used low doses of ER stress inducers at levels that allowed cell adaptation to occur in order to investigate the effect of stress response on chemoresistance. We found that prolonged tolerable ER stress promotes mesenchymal-epithelial transition, slows cell-cycle progression, and delays the S-phase exit. Consequently, cisplatin-induced apoptosis was significantly decreased in stress-adapted cells, implying their acquisition of cisplatin resistance. Molecularly, we found that proliferating cell nuclear antigen (PCNA) ubiquitination and the expression of polymerase η, the main polymerase responsible for translesion synthesis across cisplatin-DNA damage, were up-regulated in ER stress-adaptive cells, and their enhanced cisplatin resistance was abrogated by the knockout of polymerase η. We also found that a fraction of p53 in stress-adapted cells was translocated to the nucleus, and that these cells exhibited a significant decline in the level of cisplatin-DNA damage. Consistently, we showed that the nuclear p53 coincided with strong positivity of glucose-related protein 78 (GRP78) on immunostaining of clinical biopsies, and the cisplatin-based chemotherapy was less effective for patients with high levels of ER stress. Taken together, this study uncovers that adaptation to ER stress enhances DNA repair and damage tolerance, with which stressed cells gain resistance to chemotherapeutics.


Assuntos
Adaptação Fisiológica , Cisplatino/farmacologia , Reparo do DNA , DNA Polimerase Dirigida por DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos , Estresse do Retículo Endoplasmático , Neoplasias Bucais/tratamento farmacológico , Antineoplásicos/farmacologia , Apoptose , Proliferação de Células , Dano ao DNA , Replicação do DNA , DNA Polimerase Dirigida por DNA/genética , Chaperona BiP do Retículo Endoplasmático , Humanos , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Células Tumorais Cultivadas
4.
PLoS One ; 13(2): e0192355, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29401485

RESUMO

RBFOX3/NeuN is a neuronal splicing regulator involved in neural circuitry balance, as well as neurogenesis and synaptogenesis. Rbfox3 is expressed in neurons; however, in the retina, expression is restricted to cells in the ganglion cell layer and some cells of the inner nuclear layer. Rbfox3 is expressed in a layer-specific manner in the retina, which implies a functional role, however, the role of RBFOX3 in the retina is unknown. Rbfox3 homozygous knockout (Rbfox3-/-) mice exhibit deficits in visual learning; therefore, understanding the role of RBFOX3 in the retina is critical for interpreting behavioral results. We found Rbfox3 expression was developmentally regulated in the retina and specifically expressed in ganglion cells, amacrine cells and horizontal cells of the retina. We demonstrate deletion of Rbfox3 resulted in a reduction in the thickness of the inner plexiform layer of the retina, where synapses are formed. Number of ganglion cells and amacrine cells is normal with loss of Rbfox3. Innervation of retinal ganglion cells into their targeted brain regions is normal in Rbfox3-/- mice. Importantly, Rbfox3-/- mice displayed normal non-image and image forming functions. Taken together, our results suggest RBFOX3 is dispensable for visual function.


Assuntos
Proteínas do Tecido Nervoso/fisiologia , Proteínas Nucleares/fisiologia , Visão Ocular/fisiologia , Animais , Comportamento Animal , Proteínas de Ligação a DNA , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética
5.
PLoS One ; 11(10): e0164164, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27701470

RESUMO

Dysfunction of RBFOX3 has been identified in neurodevelopmental disorders such as autism spectrum disorder, cognitive impairments and epilepsy and a causal relationship with these diseases has been previously demonstrated with Rbfox3 homozygous knockout mice. Despite the importance of RBFOX3 during neurodevelopment, the function of RBFOX3 regarding neurogenesis and synaptogenesis remains unclear. To address this critical question, we profiled the developmental expression pattern of Rbfox3 in the brain of wild-type mice and analyzed brain volume, disease-relevant behaviors, neurogenesis, synaptic plasticity, and synaptogenesis in Rbfox3 homozygous knockout mice and their corresponding wild-type counterparts. Here we report that expression of Rbfox3 differs developmentally for distinct brain regions. Moreover, Rbfox3 homozygous knockout mice exhibited cold hyperalgesia and impaired cognitive abilities. Focusing on hippocampal phenotypes, we found Rbfox3 homozygous knockout mice displayed deficits in neurogenesis, which was correlated with cognitive impairments. Furthermore, RBFOX3 regulates the exons of genes with synapse-related function. Synaptic plasticity and density, which are related to cognitive behaviors, were altered in the hippocampal dentate gyrus of Rbfox3 homozygous knockout mice; synaptic plasticity decreased and the density of synapses increased. Taken together, our results demonstrate the important role of RBFOX3 during neural development and maturation. In addition, abnormalities in synaptic structure and function occur in Rbfox3 homozygous knockout mice. Our findings may offer mechanistic explanations for human brain diseases associated with dysfunctional RBFOX3.


Assuntos
Hipocampo/crescimento & desenvolvimento , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Neurogênese , Proteínas Nucleares/genética , Sinapses/metabolismo , Animais , Proteínas de Ligação a DNA , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Inativação de Genes , Humanos , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Transtornos do Neurodesenvolvimento/patologia , Plasticidade Neuronal , Proteínas Nucleares/metabolismo , Sinapses/patologia
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