scholarly journals Genetic identification Of brain cell types underlying schizophrenia

2017 ◽  
Author(s):  
Nathan G. Skene ◽  
Julien Bryois ◽  
Trygve E. Bakken ◽  
Gerome Breen ◽  
James J Crowley ◽  
...  
Keyword(s):  
Pyramidal Cells ◽  
Cell Types ◽  
Brain Cell ◽  
Common Variant ◽  
Genetic Identification ◽  
Medium Spiny Neurons ◽  
Gene Sets ◽  
The Common ◽  
The Brain ◽  
Brain Cell Types

AbstractWith few exceptions, the marked advances in knowledge about the genetic basis for schizophrenia have not converged on findings that can be confidently used for precise experimental modeling. Applying knowledge of the cellular taxonomy of the brain from single-cell RNA-sequencing, we evaluated whether the genomic loci implicated in schizophrenia map onto specific brain cell types. The common variant genomic results consistently mapped to pyramidal cells, medium spiny neurons, and certain interneurons but far less consistently to embryonic, progenitor, or glial cells. These enrichments were due to distinct sets of genes specifically expressed in each of these cell types. Many of the diverse gene sets associated with schizophrenia (including antipsychotic targets) implicate the same brain cell types. Our results provide a parsimonious explanation: the common-variant genetic results for schizophrenia point at a limited set of neurons, and the gene sets point to the same cells. While some of the genetic risk is associated with GABAergic interneurons, this risk largely does not overlap with that from projecting cells.

scholarly journals SARS-CoV-2 receptor and entry genes are expressed by sustentacular cells in the human olfactory neuroepithelium

2020 ◽  
Author(s):  
Leon Fodoulian ◽  
Joel Tuberosa ◽  
Daniel Rossier ◽  
Madlaina Boillat ◽  
Chenda Kan ◽  
...  
Keyword(s):  
Sensory System ◽  
Cell Types ◽  
Sensory Epithelium ◽  
Brain Cell ◽  
Rna Seq ◽  
Angiotensin Converting Enzyme 2 ◽  
Sustentacular Cells ◽  
The Brain ◽  
Brain Cell Types ◽  
Human And Mouse

AbstractVarious reports indicate an association between COVID-19 and anosmia, suggesting an infection of the olfactory sensory epithelium, and thus a possible direct virus access to the brain. To test this hypothesis, we generated RNA-seq libraries from human olfactory neuroepithelia, in which we found substantial expression of the genes coding for the virus receptor angiotensin-converting enzyme-2 (ACE2), and for the virus internalization enhancer TMPRSS2. We analyzed a human olfactory single-cell RNA-seq dataset and determined that sustentacular cells, which maintain the integrity of olfactory sensory neurons, express ACE2 and TMPRSS2. We then observed that the ACE2 protein was highly expressed in a subset of sustentacular cells in human and mouse olfactory tissues. Finally, we found ACE2 transcripts in specific brain cell types, both in mice and humans. Sustentacular cells thus represent a potential entry door for SARS-CoV-2 in a neuronal sensory system that is in direct connection with the brain.

scholarly journals Ultra-rare, rare, and common genetic variant analysis converge to implicate negative selection and neuronal processes in the aetiology of schizophrenia

2021 ◽  
Author(s):  
Wonuola A Akingbuwa ◽  
Anke R Hammerschlag ◽  
Meike Bartels ◽  
Michel G Nivard ◽  
Christel M Middeldorp
Keyword(s):  
Allele Frequency ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Cell Types ◽  
Brain Cell ◽  
Synaptic Function ◽  
Human Brain Tissue ◽  
Gene Sets ◽  
Cell Gene ◽  
Brain Cell Types

Both common and rare genetic variants (minor allele frequency > 1% and < 0.1% respectively) have been implicated in the aetiology of schizophrenia. In this study, we integrate single-cell gene expression data with publicly available Genome-Wide Association Study (GWAS) and exome sequenced data in order to investigate in parallel, the enrichment of common and (ultra-)rare variants related to schizophrenia in several functionally relevant gene sets. Four types of gene sets were constructed 1) protein-truncating variant (PTV)-intolerant (PI) genes 2) genes expressed in brain cell types and neurons ascertained from mouse and human brain tissue 3) genes defined by synaptic function and location and 4) intersection genes, i.e., PI genes that are expressed in the human and mouse brain cell gene sets. We show that common as well as (ultra-)rare schizophrenia-associated variants are overrepresented in PI genes, in excitatory neurons from the prefrontal cortex and hippocampus, medium spiny neurons, and genes enriched for synaptic processes. We also observed stronger enrichment in the intersection genes. Our findings suggest that across the allele frequency spectrum, genes and genetic variants likely to be under stringent selection, and those expressed in particular brain cell types, are involved in the same biological pathways influencing the risk for schizophrenia.

scholarly journals Brain Microenvironment Heterogeneity: Potential Value for Brain Tumors

2021 ◽  
Vol 11 ◽  
Author(s):  
Laura Álvaro-Espinosa ◽  
Ana de Pablos-Aragoneses ◽  
Manuel Valiente ◽  
Neibla Priego
Keyword(s):  
Brain Tumors ◽  
Single Cell ◽  
Brain Injuries ◽  
Clinical Work ◽  
Cell Types ◽  
Brain Cell ◽  
Brain Disorders ◽  
Brain Connectome ◽  
The Brain ◽  
Brain Cell Types

Uncovering the complexity of the microenvironment that emerges in brain disorders is key to identify potential vulnerabilities that might help challenging diseases affecting this organ. Recently, genomic and proteomic analyses, especially at the single cell level, have reported previously unrecognized diversity within brain cell types. The complexity of the brain microenvironment increases during disease partly due to the immune infiltration from the periphery that contributes to redefine the brain connectome by establishing a new crosstalk with resident brain cell types. Within the rewired brain ecosystem, glial cell subpopulations are emerging hubs modulating the dialogue between the Immune System and the Central Nervous System with important consequences in the progression of brain tumors and other disorders. Single cell technologies are crucial not only to define and track the origin of disease-associated cell types, but also to identify their molecular similarities and differences that might be linked to specific brain injuries. These altered molecular patterns derived from reprogramming the healthy brain into an injured organ, might provide a new generation of therapeutic targets to challenge highly prevalent and lethal brain disorders that remain incurable with unprecedented specificity and limited toxicities. In this perspective, we present the most relevant clinical and pre-clinical work regarding the characterization of the heterogeneity within different components of the microenvironment in the healthy and injured brain with a special interest on single cell analysis. Finally, we discuss how understanding the diversity of the brain microenvironment could be exploited for translational purposes, particularly in primary and secondary tumors affecting the brain.

scholarly journals Genetic identification of brain cell types underlying schizophrenia

2018 ◽  
Vol 50 (6) ◽  
pp. 825-833 ◽  
Author(s):  
Nathan G. Skene ◽  
◽  
Julien Bryois ◽  
Trygve E. Bakken ◽  
Gerome Breen ◽  
...  
Keyword(s):  
Cell Types ◽  
Brain Cell ◽  
Genetic Identification ◽  
Brain Cell Types

scholarly journals Establishment and Preliminary Characterization of Three Astrocytic Cells Lines Obtained from Primary Rat Astrocytes by Sub-Cloning

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1502
Author(s):  
Fabio Caradonna ◽  
Gabriella Schiera ◽  
Carlo Maria Di Liegro ◽  
Vincenzo Vitale ◽  
Ilenia Cruciata ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cell Types ◽  
Brain Parenchyma ◽  
Brain Cell ◽  
The Other ◽  
Cellular Events ◽  
Rat Astrocytes ◽  
The Brain ◽  
Brain Cell Types

Gliomas are complex and heterogeneous tumors that originate from the glial cells of the brain. The malignant cells undergo deep modifications of their metabolism, and acquire the capacity to invade the brain parenchyma and to induce epigenetic modifications in the other brain cell types. In spite of the efforts made to define the pathology at the molecular level, and to set novel approaches to reach the infiltrating cells, gliomas are still fatal. In order to gain a better knowledge of the cellular events that accompany astrocyte transformation, we developed three increasingly transformed astrocyte cell lines, starting from primary rat cortical astrocytes, and analyzed them at the cytogenetic and epigenetic level. In parallel, we also studied the expression of the differentiation-related H1.0 linker histone variant to evaluate its possible modification in relation with transformation. We found that the most modified astrocytes (A-FC6) have epigenetic and chromosomal alterations typical of cancer, and that the other two clones (A-GS1 and A-VV5) have intermediate properties. Surprisingly, the differentiation-specific somatic histone H1.0 steadily increases from the normal astrocytes to the most transformed ones. As a whole, our results suggest that these three cell lines, together with the starting primary cells, constitute a potential model for studying glioma development.

scholarly journals Integrative Analysis Revealed Common Genes, Brain Cell-Type and Pathways Between Stiripentol Targets and Risk Genes of Dravet Syndrome and Epilepsy

2021 ◽  
Author(s):  
Yu-qin Lv ◽  
Yu-zhuang Jiao ◽  
Yan-hua Wang ◽  
Na Wang ◽  
Lei Gao ◽  
...  
Keyword(s):  
Pyramidal Cells ◽  
Cell Types ◽  
Brain Cell ◽  
Dravet Syndrome ◽  
P Value ◽  
Cell Type ◽  
Risk Genes ◽  
Ca1 Pyramidal Cells ◽  
Hippocampal Ca1 ◽  
Brain Cell Types

Abstract Stiripentol is an anti-epileptic drug used for treating Dravet syndrome and epilepsy. To explore common molecular mechanism between antiepileptic effect of stiripentol and genetic etiology of Dravet syndrome and epilepsy, we retrieved target genes of stiripentol through DrugBank database, as well as risk genes of Dravet syndrome and epilepsy from related Database and literature research. Then we performed genetic overlap analysis, Expression Weighted Cell type Enrichment (EWCE) analysis based on single-cell RNA-sequencing (scRNA-seq) data of brain, as well as pathway enrichment analysis. A total of 23, 19 and 118 genes were retrieved for stiripentol targets, risk genes of Dravet syndrome and epilepsy respectively. For stiripentol targets and risk genes of Dravet syndrome, three genes (GABRA1, GABRB3 and GABRG2) were overlapped with P-value of 1.265×10−6; hippocampal CA1 pyramidal cells and interneurons were common brain cell types that were significantly enriched by EWCE; and 10 common pathways were identified. For stiripentol targets and risk genes of epilepsy, five genes (GABRA1, GABRA2, GABRB2, GABRB3, and GABRG2) were overlapped with P-value of 1.963 × 10−7; hippocampal CA1 pyramidal cells and interneurons were also common brain cell types that were significantly enriched and 22 common pathways were identified. Our results revealed that stiripentol might exert its anti-epileptic effect by regulating GABAA receptors on hippocampal CA1 pyramidal cells and interneurons.

scholarly journals GENETIC IDENTIFICATION OF BRAIN CELL TYPES UNDERLYING SCHIZOPHRENIA

2019 ◽  
Vol 29 ◽  
pp. S798-S799 ◽  
Author(s):  
Julien Bryois ◽  
Nathan Skene ◽  
Trygve Bakken ◽  
Gerome Breen ◽  
James Crowley ◽  
...  
Keyword(s):  
Cell Types ◽  
Brain Cell ◽  
Genetic Identification ◽  
Brain Cell Types

scholarly journals Paraoxonase-1 and -3 Protein Expression in the Brain of the Tg2576 Mouse Model of Alzheimer’s Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 339
Author(s):  
Jose Gregorio Salazar ◽  
Judit Marsillach ◽  
Ingrid Reverte ◽  
Bharti Mackness ◽  
Michael Mackness ◽  
...  
Keyword(s):  
Mouse Model ◽  
Protein Expression ◽  
Neurodegenerative Diseases ◽  
Cell Types ◽  
Brain Regions ◽  
Brain Cell ◽  
Paraoxonase 1 ◽  
Tg2576 Mouse ◽  
The Brain ◽  
Brain Cell Types

Background: Brain oxidative lipid damage and inflammation are common in neurodegenerative diseases such as Alzheimer’s disease (AD). Paraoxonase-1 and -3 (PON1 and PON3) protein expression was demonstrated in tissue with no PON1 or PON3 gene expression. In the present study, we examine differences in PON1 and PON3 protein expression in the brain of a mouse model of AD. Methods: we used peroxidase- and fluorescence-based immunohistochemistry in five brain regions (olfactory bulb, forebrain, posterior midbrain, hindbrain and cerebellum) of transgenic (Tg2576) mice with the Swedish mutation (KM670/671NL) responsible for a familial form of AD and corresponding wild-type mice. Results: We found intense PON1 and PON3-positive staining in star-shaped cells surrounding Aβ plaques in all the studied Tg2576 mouse-brain regions. Although we could not colocalize PON1 and PON3 with astrocytes (star-shaped cells in the brain), we found some PON3 colocalization with microglia. Conclusions: These results suggest that (1) PON1 and PON3 cross the blood–brain barrier in discoidal high-density lipoproteins (HDLs) and are transferred to specific brain-cell types; and (2) PON1 and PON3 play an important role in preventing oxidative stress and lipid peroxidation in particular brain-cell types (likely to be glial cells) in AD pathology and potentially in other neurodegenerative diseases as well.

scholarly journals High Vulnerability of Oligodendrocytes to Oxidative Stress Induced by Ultrafine Urban Particles

Antioxidants ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 4
Author(s):  
Ji Young Kim ◽  
Jin-Hee Kim ◽  
Yong-Dae Kim ◽  
Je Hoon Seo
Keyword(s):  
Oxidative Stress ◽  
White Matter ◽  
Cortical Neurons ◽  
Cell Types ◽  
Brain Cell ◽  
Brain Cells ◽  
Control Group ◽  
Fluoro Jade B ◽  
The Brain ◽  
Brain Cell Types

Oligodendrocytes, myelin-forming cells in the brain, are vulnerable to oxidative stress. Recent work indicates that air pollution causes demyelinating diseases such as multiple sclerosis. However, little is known about the mechanism of toxicity of ultrafine particulate matters (PMs) to oligodendrocytes. Here, we aimed to determine whether oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes (mOLs) are more vulnerable to ultrafine urban PMs (uf-UPs) than other types of brain cells and damage to adult OPCs and mOLs in the mouse brain exposed to uf-UPs. For in vitro experiments, following exposure to various concentrations (2, 20, and 200 μg/mL) of uf-UPs, we measured survival rates, the amount of reactive oxygen species (ROS), and the total antioxidant capacities (TACs) of brain cells isolated from neonatal Sprague-Dawley rats. For animal experiments, after a four-week exposure to a uf-UP suspension (20 μL, 0.4 mg/mL), we enumerated the number of damaged cells and typed damaged cells in the white matter of the cerebellum of uf-UP-exposed mice. MTT assays and Hoechst staining demonstrated that OPCs and mOLs were more vulnerable to uf-UP-induced damage than astrocytes and cortical neurons at 2, 20, and 200 μg/mL of uf-UPs examined in this study (p < 0.05). Damage to OPCs and mOLs depended on uf-UP concentration. DCF assays and DHE staining indicated that the amount of ROS generated in OPCs and mOLs was significantly higher than in other brain cell types (p < 0.05). In contrast, TAC values in OPCs and mOLs were significantly lower than those of other brain cell types (p < 0.05). Fluoro-Jade B (FJB)-positive cells in the cerebellar white matter of the uf-UP-exposed group were significantly greater in number relative to the control group. Double immunofluorescence indicated that FJB-positive cells are NG2-positive adult OPCs and carbon anhydrase II-positive mOLs. Taken together, our findings suggest that oxidative stress induced by uf-UPs in the brain impairs adult OPCs and mOLs, causing demyelination and reducing the capacity for remyelination.

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