Centre d'Information et de documentation du CRA Rhône-Alpes
CRA
Informations pratiques
-
Adresse
Centre d'information et de documentation
du CRA Rhône-Alpes
Centre Hospitalier le Vinatier
bât 211
95, Bd Pinel
69678 Bron CedexHoraires
Lundi au Vendredi
9h00-12h00 13h30-16h00Contact
Tél: +33(0)4 37 91 54 65
Mail
Fax: +33(0)4 37 91 54 37
-
Résultat de la recherche
3 recherche sur le mot-clé 'Apoptosis'
Affiner la recherche Générer le flux rss de la recherche
Partager le résultat de cette recherche Faire une suggestion
Cellular stress and apoptosis contribute to the pathogenesis of autism spectrum disorder / D. DONG in Autism Research, 11-7 (July 2018)
[article]
Titre : Cellular stress and apoptosis contribute to the pathogenesis of autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : D. DONG, Auteur ; H. R. ZIELKE, Auteur ; D. YEH, Auteur ; P. YANG, Auteur Article en page(s) : p.1076-1090 Langues : Anglais (eng) Mots-clés : apoptosis cerebellum endoplasmic reticulum stress hippocampus human autism oxidative stress prefrontal cortex Index. décimale : PER Périodiques Résumé : The molecular pathogenesis of autism spectrum disorder, a neurodevelopmental disorder, is still elusive. In this study, we investigated the possible roles of endoplasmic reticulum (ER) stress, oxidative stress, and apoptosis as molecular mechanisms underlying autism. This study compared the activation of ER stress signals (protein kinase R-like endoplasmic reticulum kinase [PERK], activating transcription factor 6 [ATF6], inositol-requiring enzyme 1 alpha [IRE1alpha]) in different brain regions (prefrontal cortex, hippocampus, cerebellum) in subjects with autism and in age-matched controls. Our data showed that the activation of three signals of ER stress varies in different regions of the autistic brain. IRE1alpha was activated in cerebellum and prefrontal cortex but ATF6 was activated in hippocampus. PERK was not activated in the three regions. Furthermore, the activation of ER stress was confirmed because the expression of C/EBP-homologous protein (CHOP), which is the common downstream indicators of ER stress signals, and most of ER chaperones were upregulated in the three regions. Consistent with the induction of ER stress, apoptosis was found in the three regions by detecting the cleavage of caspase 8 and poly(ADP-ribose) polymerase as well as using the transferase dUTP nick end labeling assay. Moreover, our data showed that oxidative stress was responsible for ER stress and apoptosis because the levels of 4-Hydroxynonenal and nitrotyrosine-modified proteins were significantly increased in the three regions. In conclusion, these data indicate that cellular stress and apoptosis may play important roles in the pathogenesis of autism. Autism Res 2018, 11: 1076-1090. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Autism results in significant morbidity and mortality in children. The functional and molecular changes in the autistic brains are unclear. The present study utilized autistic brain tissues from the National Institute of Child Health and Human Development's Brain Tissue Bank for the analysis of cellular and molecular changes in autistic brains. Three key brain regions, the hippocampus, the cerebellum, and the frontal cortex, in six cases of autistic brains and six cases of non-autistic brains from 6 to 16 years old deceased children, were analyzed. The current study investigated the possible roles of endoplasmic reticulum (ER) stress, oxidative stress, and apoptosis as molecular mechanisms underlying autism. The activation of three signals of ER stress (protein kinase R-like endoplasmic reticulum kinase, activating transcription factor 6, inositol-requiring enzyme 1 alpha) varies in different regions. The occurrence of ER stress leads to apoptosis in autistic brains. ER stress may result from oxidative stress because of elevated levels of the oxidative stress markers: 4-Hydroxynonenal and nitrotyrosine-modified proteins in autistic brains. These findings suggest that cellular stress and apoptosis may contribute to the autistic phenotype. Pharmaceuticals and/or dietary supplements, which can alleviate ER stress, oxidative stress and apoptosis, may be effective in ameliorating adverse phenotypes associated with autism. En ligne : http://dx.doi.org/10.1002/aur.1966 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=366
in Autism Research > 11-7 (July 2018) . - p.1076-1090[article] Cellular stress and apoptosis contribute to the pathogenesis of autism spectrum disorder [Texte imprimé et/ou numérique] / D. DONG, Auteur ; H. R. ZIELKE, Auteur ; D. YEH, Auteur ; P. YANG, Auteur . - p.1076-1090.
Langues : Anglais (eng)
in Autism Research > 11-7 (July 2018) . - p.1076-1090
Mots-clés : apoptosis cerebellum endoplasmic reticulum stress hippocampus human autism oxidative stress prefrontal cortex Index. décimale : PER Périodiques Résumé : The molecular pathogenesis of autism spectrum disorder, a neurodevelopmental disorder, is still elusive. In this study, we investigated the possible roles of endoplasmic reticulum (ER) stress, oxidative stress, and apoptosis as molecular mechanisms underlying autism. This study compared the activation of ER stress signals (protein kinase R-like endoplasmic reticulum kinase [PERK], activating transcription factor 6 [ATF6], inositol-requiring enzyme 1 alpha [IRE1alpha]) in different brain regions (prefrontal cortex, hippocampus, cerebellum) in subjects with autism and in age-matched controls. Our data showed that the activation of three signals of ER stress varies in different regions of the autistic brain. IRE1alpha was activated in cerebellum and prefrontal cortex but ATF6 was activated in hippocampus. PERK was not activated in the three regions. Furthermore, the activation of ER stress was confirmed because the expression of C/EBP-homologous protein (CHOP), which is the common downstream indicators of ER stress signals, and most of ER chaperones were upregulated in the three regions. Consistent with the induction of ER stress, apoptosis was found in the three regions by detecting the cleavage of caspase 8 and poly(ADP-ribose) polymerase as well as using the transferase dUTP nick end labeling assay. Moreover, our data showed that oxidative stress was responsible for ER stress and apoptosis because the levels of 4-Hydroxynonenal and nitrotyrosine-modified proteins were significantly increased in the three regions. In conclusion, these data indicate that cellular stress and apoptosis may play important roles in the pathogenesis of autism. Autism Res 2018, 11: 1076-1090. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Autism results in significant morbidity and mortality in children. The functional and molecular changes in the autistic brains are unclear. The present study utilized autistic brain tissues from the National Institute of Child Health and Human Development's Brain Tissue Bank for the analysis of cellular and molecular changes in autistic brains. Three key brain regions, the hippocampus, the cerebellum, and the frontal cortex, in six cases of autistic brains and six cases of non-autistic brains from 6 to 16 years old deceased children, were analyzed. The current study investigated the possible roles of endoplasmic reticulum (ER) stress, oxidative stress, and apoptosis as molecular mechanisms underlying autism. The activation of three signals of ER stress (protein kinase R-like endoplasmic reticulum kinase, activating transcription factor 6, inositol-requiring enzyme 1 alpha) varies in different regions. The occurrence of ER stress leads to apoptosis in autistic brains. ER stress may result from oxidative stress because of elevated levels of the oxidative stress markers: 4-Hydroxynonenal and nitrotyrosine-modified proteins in autistic brains. These findings suggest that cellular stress and apoptosis may contribute to the autistic phenotype. Pharmaceuticals and/or dietary supplements, which can alleviate ER stress, oxidative stress and apoptosis, may be effective in ameliorating adverse phenotypes associated with autism. En ligne : http://dx.doi.org/10.1002/aur.1966 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=366 Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development / S. HURLEY in Molecular Autism, 12 (2021)
[article]
Titre : Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development Type de document : Texte imprimé et/ou numérique Auteurs : S. HURLEY, Auteur ; C. MOHAN, Auteur ; P. SUETTERLIN, Auteur ; R. ELLINGFORD, Auteur ; K. L. H. RIEGMAN, Auteur ; J. ELLEGOOD, Auteur ; A. CARUSO, Auteur ; C. MICHETTI, Auteur ; O. BROCK, Auteur ; R. EVANS, Auteur ; F. RUDARI, Auteur ; A. DELOGU, Auteur ; M. L. SCATTONI, Auteur ; J. P. LERCH, Auteur ; C. FERNANDES, Auteur ; M. A. BASSON, Auteur Article en page(s) : 16 p. Langues : Anglais (eng) Mots-clés : Animals Animals, Newborn Autistic Disorder/genetics Behavior, Animal Brain/diagnostic imaging/embryology/growth & development Cell Proliferation DNA-Binding Proteins/deficiency/genetics Disease Models, Animal Female Gene Expression Regulation, Developmental Mice, Transgenic Phenotype Pregnancy Stem Cells Tumor Suppressor Protein p53/genetics Apoptosis Autism Chd8 Chromatin Conditional knockout Cortex Gene expression Hypomorph Intermediate progenitor Mouse Neural progenitor Proliferation Tbr2 p53 Pathways plc. This work is unrelated to COMPASS Pathways plc. No other competing interests to declare. Index. décimale : PER Périodiques Résumé : BACKGROUND: CHD8 haploinsufficiency causes autism and macrocephaly with high penetrance in the human population. Chd8 heterozygous mice exhibit relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. The purpose of this study was to generate new, sub-haploinsufficient Chd8 mouse models to allow us to identify and study the functions of CHD8 during embryonic cortical development. METHODS: To examine the possibility that certain phenotypes may only appear at sub-heterozygous Chd8 levels in the mouse, we created an allelic series of Chd8-deficient mice to reduce CHD8 protein levels to approximately 35% (mild hypomorph), 10% (severe hypomorph) and 0% (neural-specific conditional knockout) of wildtype levels. We used RNA sequencing to compare transcriptional dysregulation, structural MRI and brain weight to investigate effects on brain size, and cell proliferation, differentiation and apoptosis markers in immunostaining assays to quantify changes in neural progenitor fate. RESULTS: Mild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia than heterozygotes. Over 2000 genes were dysregulated in mild hypomorphs, including autism-associated neurodevelopmental and cell cycle genes. We identify increased proliferation of non-ventricular zone TBR2+ intermediate progenitors as one potential cause of brain hyperplasia in these mutants. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, including evidence for p53 pathway upregulation. In contrast to mild hypomorphs, these mice displayed reduced brain size and increased apoptosis in the embryonic neocortex. Homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in pronounced brain hypoplasia, partly caused by p53 target gene derepression and apoptosis in the embryonic neocortex. Limitations Our findings identify an important role for the autism-associated factor CHD8 in controlling the proliferation of intermediate progenitors in the mouse neocortex. We propose that CHD8 has a similar function in human brain development, but studies on human cells are required to confirm this. Because many of our mouse mutants with reduced CHD8 function die shortly after birth, it is not possible to fully determine to what extent reduced CHD8 function results in autism-associated behaviours in mice. CONCLUSIONS: Together, these findings identify important, dosage-sensitive functions for CHD8 in p53 pathway repression, neurodevelopmental gene expression and neural progenitor fate in the embryonic neocortex. We conclude that brain development is acutely sensitive to reduced CHD8 expression and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage result in non-linear effects on gene transcription and brain growth. Shaun Hurley, Conor Mohan and Philipp Suetterlin have contributed equally to this work. En ligne : http://dx.doi.org/10.1186/s13229-020-00409-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459
in Molecular Autism > 12 (2021) . - 16 p.[article] Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development [Texte imprimé et/ou numérique] / S. HURLEY, Auteur ; C. MOHAN, Auteur ; P. SUETTERLIN, Auteur ; R. ELLINGFORD, Auteur ; K. L. H. RIEGMAN, Auteur ; J. ELLEGOOD, Auteur ; A. CARUSO, Auteur ; C. MICHETTI, Auteur ; O. BROCK, Auteur ; R. EVANS, Auteur ; F. RUDARI, Auteur ; A. DELOGU, Auteur ; M. L. SCATTONI, Auteur ; J. P. LERCH, Auteur ; C. FERNANDES, Auteur ; M. A. BASSON, Auteur . - 16 p.
Langues : Anglais (eng)
in Molecular Autism > 12 (2021) . - 16 p.
Mots-clés : Animals Animals, Newborn Autistic Disorder/genetics Behavior, Animal Brain/diagnostic imaging/embryology/growth & development Cell Proliferation DNA-Binding Proteins/deficiency/genetics Disease Models, Animal Female Gene Expression Regulation, Developmental Mice, Transgenic Phenotype Pregnancy Stem Cells Tumor Suppressor Protein p53/genetics Apoptosis Autism Chd8 Chromatin Conditional knockout Cortex Gene expression Hypomorph Intermediate progenitor Mouse Neural progenitor Proliferation Tbr2 p53 Pathways plc. This work is unrelated to COMPASS Pathways plc. No other competing interests to declare. Index. décimale : PER Périodiques Résumé : BACKGROUND: CHD8 haploinsufficiency causes autism and macrocephaly with high penetrance in the human population. Chd8 heterozygous mice exhibit relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. The purpose of this study was to generate new, sub-haploinsufficient Chd8 mouse models to allow us to identify and study the functions of CHD8 during embryonic cortical development. METHODS: To examine the possibility that certain phenotypes may only appear at sub-heterozygous Chd8 levels in the mouse, we created an allelic series of Chd8-deficient mice to reduce CHD8 protein levels to approximately 35% (mild hypomorph), 10% (severe hypomorph) and 0% (neural-specific conditional knockout) of wildtype levels. We used RNA sequencing to compare transcriptional dysregulation, structural MRI and brain weight to investigate effects on brain size, and cell proliferation, differentiation and apoptosis markers in immunostaining assays to quantify changes in neural progenitor fate. RESULTS: Mild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia than heterozygotes. Over 2000 genes were dysregulated in mild hypomorphs, including autism-associated neurodevelopmental and cell cycle genes. We identify increased proliferation of non-ventricular zone TBR2+ intermediate progenitors as one potential cause of brain hyperplasia in these mutants. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, including evidence for p53 pathway upregulation. In contrast to mild hypomorphs, these mice displayed reduced brain size and increased apoptosis in the embryonic neocortex. Homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in pronounced brain hypoplasia, partly caused by p53 target gene derepression and apoptosis in the embryonic neocortex. Limitations Our findings identify an important role for the autism-associated factor CHD8 in controlling the proliferation of intermediate progenitors in the mouse neocortex. We propose that CHD8 has a similar function in human brain development, but studies on human cells are required to confirm this. Because many of our mouse mutants with reduced CHD8 function die shortly after birth, it is not possible to fully determine to what extent reduced CHD8 function results in autism-associated behaviours in mice. CONCLUSIONS: Together, these findings identify important, dosage-sensitive functions for CHD8 in p53 pathway repression, neurodevelopmental gene expression and neural progenitor fate in the embryonic neocortex. We conclude that brain development is acutely sensitive to reduced CHD8 expression and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage result in non-linear effects on gene transcription and brain growth. Shaun Hurley, Conor Mohan and Philipp Suetterlin have contributed equally to this work. En ligne : http://dx.doi.org/10.1186/s13229-020-00409-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 A multidisciplinary approach unravels early and persistent effects of X-ray exposure at the onset of prenatal neurogenesis / T. VERREET in Journal of Neurodevelopmental Disorders, 7-1 (December 2015)
[article]
Titre : A multidisciplinary approach unravels early and persistent effects of X-ray exposure at the onset of prenatal neurogenesis Type de document : Texte imprimé et/ou numérique Auteurs : T. VERREET, Auteur ; R. QUINTENS, Auteur ; D. VAN DAM, Auteur ; M. VERSLEGERS, Auteur ; M. TANORI, Auteur ; A. CASCIATI, Auteur ; M. NEEFS, Auteur ; L. LEYSEN, Auteur ; A. MICHAUX, Auteur ; A. JANSSEN, Auteur ; E. D'AGOSTINO, Auteur ; G. VANDE VELDE, Auteur ; S. BAATOUT, Auteur ; L. MOONS, Auteur ; S. PAZZAGLIA, Auteur ; A. SARAN, Auteur ; U. HIMMELREICH, Auteur ; P. P. DE DEYN, Auteur ; M. A. BENOTMANE, Auteur Article en page(s) : p.3 Langues : Anglais (eng) Mots-clés : Apoptosis Brain development Cognitive dysfunction Mri Radiation Index. décimale : PER Périodiques Résumé : BACKGROUND: In humans, in utero exposure to ionising radiation results in an increased prevalence of neurological aberrations, such as small head size, mental retardation and decreased IQ levels. Yet, the association between early damaging events and long-term neuronal anomalies remains largely elusive. METHODS: Mice were exposed to different X-ray doses, ranging between 0.0 and 1.0 Gy, at embryonic days (E) 10, 11 or 12 and subjected to behavioural tests at 12 weeks of age. Underlying mechanisms of irradiation at E11 were further unravelled using magnetic resonance imaging (MRI) and spectroscopy, diffusion tensor imaging, gene expression profiling, histology and immunohistochemistry. RESULTS: Irradiation at the onset of neurogenesis elicited behavioural changes in young adult mice, dependent on the timing of exposure. As locomotor behaviour and hippocampal-dependent spatial learning and memory were most particularly affected after irradiation at E11 with 1.0 Gy, this condition was used for further mechanistic analyses, focusing on the cerebral cortex and hippocampus. A classical p53-mediated apoptotic response was found shortly after exposure. Strikingly, in the neocortex, the majority of apoptotic and microglial cells were residing in the outer layer at 24 h after irradiation, suggesting cell death occurrence in differentiating neurons rather than proliferating cells. Furthermore, total brain volume, cortical thickness and ventricle size were decreased in the irradiated embryos. At 40 weeks of age, MRI showed that the ventricles were enlarged whereas N-acetyl aspartate concentrations and functional anisotropy were reduced in the cortex of the irradiated animals, indicating a decrease in neuronal cell number and persistent neuroinflammation. Finally, in the hippocampus, we revealed a reduction in general neurogenic proliferation and in the amount of Sox2-positive precursors after radiation exposure, although only at a juvenile age. CONCLUSIONS: Our findings provide evidence for a radiation-induced disruption of mouse brain development, resulting in behavioural differences. We propose that alterations in cortical morphology and juvenile hippocampal neurogenesis might both contribute to the observed aberrant behaviour. Furthermore, our results challenge the generally assumed view of a higher radiosensitivity in dividing cells. Overall, this study offers new insights into irradiation-dependent effects in the embryonic brain, of relevance for the neurodevelopmental and radiobiological field. En ligne : http://dx.doi.org/10.1186/1866-1955-7-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=347
in Journal of Neurodevelopmental Disorders > 7-1 (December 2015) . - p.3[article] A multidisciplinary approach unravels early and persistent effects of X-ray exposure at the onset of prenatal neurogenesis [Texte imprimé et/ou numérique] / T. VERREET, Auteur ; R. QUINTENS, Auteur ; D. VAN DAM, Auteur ; M. VERSLEGERS, Auteur ; M. TANORI, Auteur ; A. CASCIATI, Auteur ; M. NEEFS, Auteur ; L. LEYSEN, Auteur ; A. MICHAUX, Auteur ; A. JANSSEN, Auteur ; E. D'AGOSTINO, Auteur ; G. VANDE VELDE, Auteur ; S. BAATOUT, Auteur ; L. MOONS, Auteur ; S. PAZZAGLIA, Auteur ; A. SARAN, Auteur ; U. HIMMELREICH, Auteur ; P. P. DE DEYN, Auteur ; M. A. BENOTMANE, Auteur . - p.3.
Langues : Anglais (eng)
in Journal of Neurodevelopmental Disorders > 7-1 (December 2015) . - p.3
Mots-clés : Apoptosis Brain development Cognitive dysfunction Mri Radiation Index. décimale : PER Périodiques Résumé : BACKGROUND: In humans, in utero exposure to ionising radiation results in an increased prevalence of neurological aberrations, such as small head size, mental retardation and decreased IQ levels. Yet, the association between early damaging events and long-term neuronal anomalies remains largely elusive. METHODS: Mice were exposed to different X-ray doses, ranging between 0.0 and 1.0 Gy, at embryonic days (E) 10, 11 or 12 and subjected to behavioural tests at 12 weeks of age. Underlying mechanisms of irradiation at E11 were further unravelled using magnetic resonance imaging (MRI) and spectroscopy, diffusion tensor imaging, gene expression profiling, histology and immunohistochemistry. RESULTS: Irradiation at the onset of neurogenesis elicited behavioural changes in young adult mice, dependent on the timing of exposure. As locomotor behaviour and hippocampal-dependent spatial learning and memory were most particularly affected after irradiation at E11 with 1.0 Gy, this condition was used for further mechanistic analyses, focusing on the cerebral cortex and hippocampus. A classical p53-mediated apoptotic response was found shortly after exposure. Strikingly, in the neocortex, the majority of apoptotic and microglial cells were residing in the outer layer at 24 h after irradiation, suggesting cell death occurrence in differentiating neurons rather than proliferating cells. Furthermore, total brain volume, cortical thickness and ventricle size were decreased in the irradiated embryos. At 40 weeks of age, MRI showed that the ventricles were enlarged whereas N-acetyl aspartate concentrations and functional anisotropy were reduced in the cortex of the irradiated animals, indicating a decrease in neuronal cell number and persistent neuroinflammation. Finally, in the hippocampus, we revealed a reduction in general neurogenic proliferation and in the amount of Sox2-positive precursors after radiation exposure, although only at a juvenile age. CONCLUSIONS: Our findings provide evidence for a radiation-induced disruption of mouse brain development, resulting in behavioural differences. We propose that alterations in cortical morphology and juvenile hippocampal neurogenesis might both contribute to the observed aberrant behaviour. Furthermore, our results challenge the generally assumed view of a higher radiosensitivity in dividing cells. Overall, this study offers new insights into irradiation-dependent effects in the embryonic brain, of relevance for the neurodevelopmental and radiobiological field. En ligne : http://dx.doi.org/10.1186/1866-1955-7-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=347