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Profiling olfactory stem cells from living patients identifies miRNAs relevant for autism pathophysiology / L. S. NGUYEN in Molecular Autism, 7 (2016)
[article]
Titre : Profiling olfactory stem cells from living patients identifies miRNAs relevant for autism pathophysiology Type de document : Texte imprimé et/ou numérique Auteurs : L. S. NGUYEN, Auteur ; M. LEPLEUX, Auteur ; M. MAKHLOUF, Auteur ; C. MARTIN, Auteur ; J. FREGEAC, Auteur ; K. SIQUIER-PERNET, Auteur ; A. PHILIPPE, Auteur ; F. FERON, Auteur ; B. GEPNER, Auteur ; C. ROUGEULLE, Auteur ; Y. HUMEAU, Auteur ; L. COLLEAUX, Auteur Article en page(s) : 1p. Langues : Anglais (eng) Mots-clés : 3' Untranslated Regions/genetics Adult Adult Stem Cells/metabolism Animals Astrocytes/metabolism Autism Spectrum Disorder/genetics/pathology/physiopathology Cells, Cultured Female Fibroblasts/metabolism Genetic Vectors/genetics Hippocampus/cytology/embryology Humans Lentivirus/genetics Male Mice MicroRNAs/genetics/physiology Neurons/metabolism/ultrastructure Olfactory Mucosa/pathology Organ Specificity Real-Time Polymerase Chain Reaction Transcriptome Young Adult Astrocyte Autism spectrum disorders MicroRNA Neuron Olfactory mucosa stem cells Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders caused by the interaction between genetic vulnerability and environmental factors. MicroRNAs (miRNAs) are key posttranscriptional regulators involved in multiple aspects of brain development and function. Previous studies have investigated miRNAs expression in ASD using non-neural cells like lymphoblastoid cell lines (LCL) or postmortem tissues. However, the relevance of LCLs is questionable in the context of a neurodevelopmental disorder, and the impact of the cause of death and/or post-death handling of tissue likely contributes to the variations observed between studies on brain samples. METHODS: miRNA profiling using TLDA high-throughput real-time qPCR was performed on miRNAs extracted from olfactory mucosal stem cells (OMSCs) biopsied from eight patients and six controls. This tissue is considered as a closer tissue to neural stem cells that could be sampled in living patients and was never investigated for such a purpose before. Real-time PCR was used to validate a set of differentially expressed miRNAs, and bioinformatics analysis determined common pathways and gene targets. Luciferase assays and real-time PCR analysis were used to evaluate the effect of miRNAs misregulation on the expression and translation of several autism-related transcripts. Viral vector-mediated expression was used to evaluate the impact of miRNAs deregulation on neuronal or glial cells functions. RESULTS: We identified a signature of four miRNAs (miR-146a, miR-221, miR-654-5p, and miR-656) commonly deregulated in ASD. This signature is conserved in primary skin fibroblasts and may allow discriminating between ASD and intellectual disability samples. Putative target genes of the differentially expressed miRNAs were enriched for pathways previously associated to ASD, and altered levels of neuronal transcripts targeted by miR-146a, miR-221, and miR-656 were observed in patients' cells. In the mouse brain, miR-146a, and miR-221 display strong neuronal expression in regions important for high cognitive functions, and we demonstrated that reproducing abnormal miR-146a expression in mouse primary cell cultures leads to impaired neuronal dendritic arborization and increased astrocyte glutamate uptake capacities. CONCLUSIONS: While independent replication experiments are needed to clarify whether these four miRNAS could serve as early biomarkers of ASD, these findings may have important diagnostic implications. They also provide mechanistic connection between miRNA dysregulation and ASD pathophysiology and may open up new opportunities for therapeutic. En ligne : http://dx.doi.org/10.1186/s13229-015-0064-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328
in Molecular Autism > 7 (2016) . - 1p.[article] Profiling olfactory stem cells from living patients identifies miRNAs relevant for autism pathophysiology [Texte imprimé et/ou numérique] / L. S. NGUYEN, Auteur ; M. LEPLEUX, Auteur ; M. MAKHLOUF, Auteur ; C. MARTIN, Auteur ; J. FREGEAC, Auteur ; K. SIQUIER-PERNET, Auteur ; A. PHILIPPE, Auteur ; F. FERON, Auteur ; B. GEPNER, Auteur ; C. ROUGEULLE, Auteur ; Y. HUMEAU, Auteur ; L. COLLEAUX, Auteur . - 1p.
Langues : Anglais (eng)
in Molecular Autism > 7 (2016) . - 1p.
Mots-clés : 3' Untranslated Regions/genetics Adult Adult Stem Cells/metabolism Animals Astrocytes/metabolism Autism Spectrum Disorder/genetics/pathology/physiopathology Cells, Cultured Female Fibroblasts/metabolism Genetic Vectors/genetics Hippocampus/cytology/embryology Humans Lentivirus/genetics Male Mice MicroRNAs/genetics/physiology Neurons/metabolism/ultrastructure Olfactory Mucosa/pathology Organ Specificity Real-Time Polymerase Chain Reaction Transcriptome Young Adult Astrocyte Autism spectrum disorders MicroRNA Neuron Olfactory mucosa stem cells Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders caused by the interaction between genetic vulnerability and environmental factors. MicroRNAs (miRNAs) are key posttranscriptional regulators involved in multiple aspects of brain development and function. Previous studies have investigated miRNAs expression in ASD using non-neural cells like lymphoblastoid cell lines (LCL) or postmortem tissues. However, the relevance of LCLs is questionable in the context of a neurodevelopmental disorder, and the impact of the cause of death and/or post-death handling of tissue likely contributes to the variations observed between studies on brain samples. METHODS: miRNA profiling using TLDA high-throughput real-time qPCR was performed on miRNAs extracted from olfactory mucosal stem cells (OMSCs) biopsied from eight patients and six controls. This tissue is considered as a closer tissue to neural stem cells that could be sampled in living patients and was never investigated for such a purpose before. Real-time PCR was used to validate a set of differentially expressed miRNAs, and bioinformatics analysis determined common pathways and gene targets. Luciferase assays and real-time PCR analysis were used to evaluate the effect of miRNAs misregulation on the expression and translation of several autism-related transcripts. Viral vector-mediated expression was used to evaluate the impact of miRNAs deregulation on neuronal or glial cells functions. RESULTS: We identified a signature of four miRNAs (miR-146a, miR-221, miR-654-5p, and miR-656) commonly deregulated in ASD. This signature is conserved in primary skin fibroblasts and may allow discriminating between ASD and intellectual disability samples. Putative target genes of the differentially expressed miRNAs were enriched for pathways previously associated to ASD, and altered levels of neuronal transcripts targeted by miR-146a, miR-221, and miR-656 were observed in patients' cells. In the mouse brain, miR-146a, and miR-221 display strong neuronal expression in regions important for high cognitive functions, and we demonstrated that reproducing abnormal miR-146a expression in mouse primary cell cultures leads to impaired neuronal dendritic arborization and increased astrocyte glutamate uptake capacities. CONCLUSIONS: While independent replication experiments are needed to clarify whether these four miRNAS could serve as early biomarkers of ASD, these findings may have important diagnostic implications. They also provide mechanistic connection between miRNA dysregulation and ASD pathophysiology and may open up new opportunities for therapeutic. En ligne : http://dx.doi.org/10.1186/s13229-015-0064-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328 The Autism-Related lncRNA MSNP1AS Regulates Moesin Protein to Influence the RhoA, Rac1, and PI3K/Akt Pathways and Regulate the Structure and Survival of Neurons / Ting LUO in Autism Research, 13-12 (December 2020)
[article]
Titre : The Autism-Related lncRNA MSNP1AS Regulates Moesin Protein to Influence the RhoA, Rac1, and PI3K/Akt Pathways and Regulate the Structure and Survival of Neurons Type de document : Texte imprimé et/ou numérique Auteurs : Ting LUO, Auteur ; Jin-Nan OU, Auteur ; Li-Fang CAO, Auteur ; Xiao-Qing PENG, Auteur ; Ya-Min LI, Auteur ; Yong-Quan TIAN, Auteur Article en page(s) : p.2073-2082 Langues : Anglais (eng) Mots-clés : Msnp1as autism spectrum disorder lncRNA neuron Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a complex disease involving multiple genes and multiple sites, and it is closely related to environmental factors. It has been gradually revealed that long noncoding RNAs (lncRNAs) may regulate the pathogenesis of ASD at the epigenetic level. In neuronal cells, the lncRNA moesin pseudogene 1 antisense (MSNP1AS) forms a double-stranded RNA with moesin (MSN) to suppress moesin protein expression. MSNP1AS overexpression can activate the RhoA pathway and inhibit the Rac1 and PI3K/Akt pathways; however, the regulation of Rac1 by MSNP1AS is not associated with MSN, and the effect on the RhoA pathway may also be associated with other factors. MSNP1AS can decrease the number and length of neurites, inhibit neuronal cell viability and migration, and promote apoptosis. Downregulation of MSN expression functions similarly to MSNP1AS, and its overexpression can block the above functions of MSNP1AS. In addition, in vivo experiments show that MSN improves social interactions and reduces repetitive behaviors in BTBR mice, decreases the activity of RhoA and restores the activity of PI3K/Akt pathway. Therefore, the abnormal expression of MSNP1AS in ASD patients might influence the structure and survival of neuronal cells through the regulation of moesin protein expression to facilitate the development and progression of ASD. These findings provide new evidence for studying the mechanisms of lncRNAs in ASD. LAY SUMMARY: Autism spectrum disorder (ASD) is a common neurodevelopmental disease and its neurodevelopmental mechanisms have not been elucidated. More and more studies have found that long noncoding RNAs (lncRNAs) can regulate the development of central nervous system in many ways and affect the pathogenic process of ASD. Moesin pseudogene 1 antisense (MSNP1AS) is an up-regulated lncRNA in ASD patients. In-depth functional experiments showed that MSNP1AS inhibited moesin protein expression and regulated the activation of multiple signaling pathways, thus decreasing the number and length of neurites, inhibiting neuronal cell viability and migration, and promoting apoptosis. Therefore, MSNP1AS is an important lncRNA related to ASD and can regulate the biological function of neurons. En ligne : http://dx.doi.org/10.1002/aur.2413 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=434
in Autism Research > 13-12 (December 2020) . - p.2073-2082[article] The Autism-Related lncRNA MSNP1AS Regulates Moesin Protein to Influence the RhoA, Rac1, and PI3K/Akt Pathways and Regulate the Structure and Survival of Neurons [Texte imprimé et/ou numérique] / Ting LUO, Auteur ; Jin-Nan OU, Auteur ; Li-Fang CAO, Auteur ; Xiao-Qing PENG, Auteur ; Ya-Min LI, Auteur ; Yong-Quan TIAN, Auteur . - p.2073-2082.
Langues : Anglais (eng)
in Autism Research > 13-12 (December 2020) . - p.2073-2082
Mots-clés : Msnp1as autism spectrum disorder lncRNA neuron Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a complex disease involving multiple genes and multiple sites, and it is closely related to environmental factors. It has been gradually revealed that long noncoding RNAs (lncRNAs) may regulate the pathogenesis of ASD at the epigenetic level. In neuronal cells, the lncRNA moesin pseudogene 1 antisense (MSNP1AS) forms a double-stranded RNA with moesin (MSN) to suppress moesin protein expression. MSNP1AS overexpression can activate the RhoA pathway and inhibit the Rac1 and PI3K/Akt pathways; however, the regulation of Rac1 by MSNP1AS is not associated with MSN, and the effect on the RhoA pathway may also be associated with other factors. MSNP1AS can decrease the number and length of neurites, inhibit neuronal cell viability and migration, and promote apoptosis. Downregulation of MSN expression functions similarly to MSNP1AS, and its overexpression can block the above functions of MSNP1AS. In addition, in vivo experiments show that MSN improves social interactions and reduces repetitive behaviors in BTBR mice, decreases the activity of RhoA and restores the activity of PI3K/Akt pathway. Therefore, the abnormal expression of MSNP1AS in ASD patients might influence the structure and survival of neuronal cells through the regulation of moesin protein expression to facilitate the development and progression of ASD. These findings provide new evidence for studying the mechanisms of lncRNAs in ASD. LAY SUMMARY: Autism spectrum disorder (ASD) is a common neurodevelopmental disease and its neurodevelopmental mechanisms have not been elucidated. More and more studies have found that long noncoding RNAs (lncRNAs) can regulate the development of central nervous system in many ways and affect the pathogenic process of ASD. Moesin pseudogene 1 antisense (MSNP1AS) is an up-regulated lncRNA in ASD patients. In-depth functional experiments showed that MSNP1AS inhibited moesin protein expression and regulated the activation of multiple signaling pathways, thus decreasing the number and length of neurites, inhibiting neuronal cell viability and migration, and promoting apoptosis. Therefore, MSNP1AS is an important lncRNA related to ASD and can regulate the biological function of neurons. En ligne : http://dx.doi.org/10.1002/aur.2413 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=434 The Autistic Spectrum Disorders (ASD): From the Clinics to the Molecular Analysis / Pierre L. ROUBERTOUX
Titre : The Autistic Spectrum Disorders (ASD): From the Clinics to the Molecular Analysis Type de document : Texte imprimé et/ou numérique Auteurs : Pierre L. ROUBERTOUX, Auteur ; Sylvie TORDJMAN, Auteur Année de publication : 2015 Importance : p.29-66 Langues : Anglais (eng) Mots-clés : Autism Rare diseases DSM Synapse Neuron Genes Gene homology Transcription Signaling pathways Index. décimale : AUT-B AUT-B - L'Autisme - Ouvrages généraux et scientifiques Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=265 The Autistic Spectrum Disorders (ASD): From the Clinics to the Molecular Analysis [Texte imprimé et/ou numérique] / Pierre L. ROUBERTOUX, Auteur ; Sylvie TORDJMAN, Auteur . - 2015 . - p.29-66.
Langues : Anglais (eng)
Mots-clés : Autism Rare diseases DSM Synapse Neuron Genes Gene homology Transcription Signaling pathways Index. décimale : AUT-B AUT-B - L'Autisme - Ouvrages généraux et scientifiques Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=265 Exemplaires
Code-barres Cote Support Localisation Section Disponibilité aucun exemplaire The role of reduced expression of fragile X mental retardation protein in neurons and increased expression in astrocytes in idiopathic and syndromic autism (duplications 15q11.2-q13) in Autism Research, 11-10 (October 2018)
[article]
Titre : The role of reduced expression of fragile X mental retardation protein in neurons and increased expression in astrocytes in idiopathic and syndromic autism (duplications 15q11.2-q13) Type de document : Texte imprimé et/ou numérique Article en page(s) : p.1316-1331 Langues : Anglais (eng) Mots-clés : astrocyte duplication 15q11.2-q13/autism fragile X mental retardation protein idiopathic autism neuron Index. décimale : PER Périodiques Résumé : Fragile X syndrome (FXS), caused by lack of fragile X mental retardation protein (FMRP), is associated with a high prevalence of autism. The deficit of FMRP reported in idiopathic autism suggests a mechanistic overlap between FXS and autism. The overall goal of this study is to detect neuropathological commonalities of FMRP deficits in the brains of people with idiopathic autism and with syndromic autism caused by dup15q11.2-q13 (dup15). This study tests the hypothesis based on our preliminary data that both idiopathic and syndromic autism are associated with brain region-specific deficits of neuronal FMRP and structural changes of the affected neurons. This immunocytochemical study revealed neuronal FMRP deficits and shrinkage of deficient neurons in the cerebral cortex, subcortical structures, and cerebellum in subjects with idiopathic and dup(15)/autism. Neuronal FMRP deficit coexists with surprising infiltration of the brains of autistic children and adults with FMRP-positive astrocytes known to be typical only for the fetal and short postnatal periods. In the examined autistic subjects, these astrocytes selectively infiltrate the border between white and gray matter in the cerebral and cerebellar cortex, the molecular layer of the cortex, part of the amygdala and thalamus, central cerebellar white matter, and dentate nucleus. Astrocyte pathology results in an additional local loss of FMRP in neurons and their shrinkage. Neuronal deficit of FMRP and shrinkage of affected neurons in structures free of FMRP-positive astrocytes and regions infiltrated with FMRP-expressing astrocytes appear to reflect mechanistic, neuropathological, and functional commonalities of FMRP abnormalities in FXS and autism spectrum disorder. Autism Res 2018, 11: 1316-1331. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Immunocytochemistry reveals a deficit of fragile X mental retardation protein (FMRP) in neurons of cortical and subcortical brain structures but increased FMRP expression in astrocytes infiltrating gray and white matter. The detected shrinkage of FMRP-deficient neurons may provide a mechanistic explanation of reported neuronal structural and functional changes in autism. This study contributes to growing evidence of mechanistic commonalities between fragile X syndrome and autism spectrum disorder. En ligne : http://dx.doi.org/10.1002/aur.2003 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=369
in Autism Research > 11-10 (October 2018) . - p.1316-1331[article] The role of reduced expression of fragile X mental retardation protein in neurons and increased expression in astrocytes in idiopathic and syndromic autism (duplications 15q11.2-q13) [Texte imprimé et/ou numérique] . - p.1316-1331.
Langues : Anglais (eng)
in Autism Research > 11-10 (October 2018) . - p.1316-1331
Mots-clés : astrocyte duplication 15q11.2-q13/autism fragile X mental retardation protein idiopathic autism neuron Index. décimale : PER Périodiques Résumé : Fragile X syndrome (FXS), caused by lack of fragile X mental retardation protein (FMRP), is associated with a high prevalence of autism. The deficit of FMRP reported in idiopathic autism suggests a mechanistic overlap between FXS and autism. The overall goal of this study is to detect neuropathological commonalities of FMRP deficits in the brains of people with idiopathic autism and with syndromic autism caused by dup15q11.2-q13 (dup15). This study tests the hypothesis based on our preliminary data that both idiopathic and syndromic autism are associated with brain region-specific deficits of neuronal FMRP and structural changes of the affected neurons. This immunocytochemical study revealed neuronal FMRP deficits and shrinkage of deficient neurons in the cerebral cortex, subcortical structures, and cerebellum in subjects with idiopathic and dup(15)/autism. Neuronal FMRP deficit coexists with surprising infiltration of the brains of autistic children and adults with FMRP-positive astrocytes known to be typical only for the fetal and short postnatal periods. In the examined autistic subjects, these astrocytes selectively infiltrate the border between white and gray matter in the cerebral and cerebellar cortex, the molecular layer of the cortex, part of the amygdala and thalamus, central cerebellar white matter, and dentate nucleus. Astrocyte pathology results in an additional local loss of FMRP in neurons and their shrinkage. Neuronal deficit of FMRP and shrinkage of affected neurons in structures free of FMRP-positive astrocytes and regions infiltrated with FMRP-expressing astrocytes appear to reflect mechanistic, neuropathological, and functional commonalities of FMRP abnormalities in FXS and autism spectrum disorder. Autism Res 2018, 11: 1316-1331. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Immunocytochemistry reveals a deficit of fragile X mental retardation protein (FMRP) in neurons of cortical and subcortical brain structures but increased FMRP expression in astrocytes infiltrating gray and white matter. The detected shrinkage of FMRP-deficient neurons may provide a mechanistic explanation of reported neuronal structural and functional changes in autism. This study contributes to growing evidence of mechanistic commonalities between fragile X syndrome and autism spectrum disorder. En ligne : http://dx.doi.org/10.1002/aur.2003 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=369