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Quantitative proteomic analysis of Rett iPSC-derived neuronal progenitors / Suzy VARDERIDOU-MINASIAN in Molecular Autism, 11 (2020)
[article]
Titre : Quantitative proteomic analysis of Rett iPSC-derived neuronal progenitors Type de document : Texte imprimé et/ou numérique Auteurs : Suzy VARDERIDOU-MINASIAN, Auteur ; Lisa HINZ, Auteur ; Dominique HAGEMANS, Auteur ; Daniëlle POSTHUMA, Auteur ; Maarten ALTELAAR, Auteur ; Vivi M. HEINE, Auteur Article en page(s) : 38 p. Langues : Anglais (eng) Mots-clés : Neuron differentiation Quantitative mass spectrometry Rett syndrome TMT-10plex iPSC Index. décimale : PER Périodiques Résumé : BACKGROUND: Rett syndrome (RTT) is a progressive neurodevelopmental disease that is characterized by abnormalities in cognitive, social, and motor skills. RTT is often caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). The mechanism by which impaired MeCP2 induces the pathological abnormalities in the brain is not understood. Both patients and mouse models have shown abnormalities at molecular and cellular level before typical RTT-associated symptoms appear. This implies that underlying mechanisms are already affected during neurodevelopmental stages. METHODS: To understand the molecular mechanisms involved in disease onset, we used an RTT patient induced pluripotent stem cell (iPSC)-based model with isogenic controls and performed time-series of proteomic analysis using in-depth high-resolution quantitative mass spectrometry during early stages of neuronal development. RESULTS: We provide mass spectrometry-based quantitative proteomic data, depth of about 7000 proteins, at neuronal progenitor developmental stages of RTT patient cells and isogenic controls. Our data gives evidence of proteomic alteration at early neurodevelopmental stages, suggesting alterations long before the phase that symptoms of RTT syndrome become apparent. Significant changes are associated with the GO enrichment analysis in biological processes cell-cell adhesion, actin cytoskeleton organization, neuronal stem cell population maintenance, and pituitary gland development, next to protein changes previously associated with RTT, i.e., dendrite morphology and synaptic deficits. Differential expression increased from early to late neural stem cell phases, although proteins involved in immunity, metabolic processes, and calcium signaling were affected throughout all stages analyzed. LIMITATIONS: The limitation of our study is the number of RTT patients analyzed. As the aim of our study was to investigate a large number of proteins, only one patient was considered, of which 3 different RTT iPSC clones and 3 isogenic control iPSC clones were included. Even though this approach allowed the study of mutation-induced alterations due to the usage of isogenic controls, results should be validated on different RTT patients to suggest common disease mechanisms. CONCLUSIONS: During early neuronal differentiation, there are consistent and time-point specific proteomic alterations in RTT patient cells carrying exons 3-4 deletion in MECP2. We found changes in proteins involved in pathway associated with RTT phenotypes, including dendrite morphology and synaptogenesis. Our results provide a valuable resource of proteins and pathways for follow-up studies, investigating common mechanisms involved during early disease stages of RTT syndrome. En ligne : http://dx.doi.org/10.1186/s13229-020-00344-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427
in Molecular Autism > 11 (2020) . - 38 p.[article] Quantitative proteomic analysis of Rett iPSC-derived neuronal progenitors [Texte imprimé et/ou numérique] / Suzy VARDERIDOU-MINASIAN, Auteur ; Lisa HINZ, Auteur ; Dominique HAGEMANS, Auteur ; Daniëlle POSTHUMA, Auteur ; Maarten ALTELAAR, Auteur ; Vivi M. HEINE, Auteur . - 38 p.
Langues : Anglais (eng)
in Molecular Autism > 11 (2020) . - 38 p.
Mots-clés : Neuron differentiation Quantitative mass spectrometry Rett syndrome TMT-10plex iPSC Index. décimale : PER Périodiques Résumé : BACKGROUND: Rett syndrome (RTT) is a progressive neurodevelopmental disease that is characterized by abnormalities in cognitive, social, and motor skills. RTT is often caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). The mechanism by which impaired MeCP2 induces the pathological abnormalities in the brain is not understood. Both patients and mouse models have shown abnormalities at molecular and cellular level before typical RTT-associated symptoms appear. This implies that underlying mechanisms are already affected during neurodevelopmental stages. METHODS: To understand the molecular mechanisms involved in disease onset, we used an RTT patient induced pluripotent stem cell (iPSC)-based model with isogenic controls and performed time-series of proteomic analysis using in-depth high-resolution quantitative mass spectrometry during early stages of neuronal development. RESULTS: We provide mass spectrometry-based quantitative proteomic data, depth of about 7000 proteins, at neuronal progenitor developmental stages of RTT patient cells and isogenic controls. Our data gives evidence of proteomic alteration at early neurodevelopmental stages, suggesting alterations long before the phase that symptoms of RTT syndrome become apparent. Significant changes are associated with the GO enrichment analysis in biological processes cell-cell adhesion, actin cytoskeleton organization, neuronal stem cell population maintenance, and pituitary gland development, next to protein changes previously associated with RTT, i.e., dendrite morphology and synaptic deficits. Differential expression increased from early to late neural stem cell phases, although proteins involved in immunity, metabolic processes, and calcium signaling were affected throughout all stages analyzed. LIMITATIONS: The limitation of our study is the number of RTT patients analyzed. As the aim of our study was to investigate a large number of proteins, only one patient was considered, of which 3 different RTT iPSC clones and 3 isogenic control iPSC clones were included. Even though this approach allowed the study of mutation-induced alterations due to the usage of isogenic controls, results should be validated on different RTT patients to suggest common disease mechanisms. CONCLUSIONS: During early neuronal differentiation, there are consistent and time-point specific proteomic alterations in RTT patient cells carrying exons 3-4 deletion in MECP2. We found changes in proteins involved in pathway associated with RTT phenotypes, including dendrite morphology and synaptogenesis. Our results provide a valuable resource of proteins and pathways for follow-up studies, investigating common mechanisms involved during early disease stages of RTT syndrome. En ligne : http://dx.doi.org/10.1186/s13229-020-00344-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 Drug Studies on Rett Syndrome: From Bench to Bedside / Mohan GOMATHI in Journal of Autism and Developmental Disorders, 50-8 (August 2020)
[article]
Titre : Drug Studies on Rett Syndrome: From Bench to Bedside Type de document : Texte imprimé et/ou numérique Auteurs : Mohan GOMATHI, Auteur ; Subramanian PADMAPRIYA, Auteur ; Vellingiri BALACHANDAR, Auteur Article en page(s) : p.2740-2764 Langues : Anglais (eng) Mots-clés : Clinical trials Drug discovery MECP2 knockout mice Non-clinical studies Rett syndrome iPSC Index. décimale : PER Périodiques Résumé : Drug studies on Rett syndrome (RTT) have drastically increased over the past few decades. This review aims to provide master data on bench-to-bedside drug studies involving RTT. A comprehensive literature review was performed by searching in PUBMED, MEDLINE and Google Scholar, international, national and regional clinical trial registries and pharmaceutical companies using the keywords "Rett syndrome treatment and/or drug or compound or molecule". Seventy drugs were investigated in non-clinical (N?=?65 animal/cell line-based studies; N?=?5 iPSC-based study) and clinical trials (N?=?34) for ameliorating the symptoms of RTT. Though there is good progress in both clinical and non-clinical studies, none of these drugs entered phase III/IV for being launched as a therapeutic agent for RTT. En ligne : http://dx.doi.org/10.1007/s10803-020-04381-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=428
in Journal of Autism and Developmental Disorders > 50-8 (August 2020) . - p.2740-2764[article] Drug Studies on Rett Syndrome: From Bench to Bedside [Texte imprimé et/ou numérique] / Mohan GOMATHI, Auteur ; Subramanian PADMAPRIYA, Auteur ; Vellingiri BALACHANDAR, Auteur . - p.2740-2764.
Langues : Anglais (eng)
in Journal of Autism and Developmental Disorders > 50-8 (August 2020) . - p.2740-2764
Mots-clés : Clinical trials Drug discovery MECP2 knockout mice Non-clinical studies Rett syndrome iPSC Index. décimale : PER Périodiques Résumé : Drug studies on Rett syndrome (RTT) have drastically increased over the past few decades. This review aims to provide master data on bench-to-bedside drug studies involving RTT. A comprehensive literature review was performed by searching in PUBMED, MEDLINE and Google Scholar, international, national and regional clinical trial registries and pharmaceutical companies using the keywords "Rett syndrome treatment and/or drug or compound or molecule". Seventy drugs were investigated in non-clinical (N?=?65 animal/cell line-based studies; N?=?5 iPSC-based study) and clinical trials (N?=?34) for ameliorating the symptoms of RTT. Though there is good progress in both clinical and non-clinical studies, none of these drugs entered phase III/IV for being launched as a therapeutic agent for RTT. En ligne : http://dx.doi.org/10.1007/s10803-020-04381-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=428 Complexities of X chromosome inactivation status in female human induced pluripotent stem cells-a brief review and scientific update for autism research / M. G. DANDULAKIS in Journal of Neurodevelopmental Disorders, 8-1 (December 2016)
[article]
Titre : Complexities of X chromosome inactivation status in female human induced pluripotent stem cells-a brief review and scientific update for autism research Type de document : Texte imprimé et/ou numérique Auteurs : M. G. DANDULAKIS, Auteur ; K. MEGANATHAN, Auteur ; K. L. KROLL, Auteur ; A. BONNI, Auteur ; John N. CONSTANTINO, Auteur Article en page(s) : p.22 Langues : Anglais (eng) Mots-clés : Asd Autism Developmental disorders X chromosome X-inactivation X-linked ASD X-reactivation iPSC "Female protective effect" Index. décimale : PER Périodiques Résumé : Induced pluripotent stem cells (iPSCs) allow researchers to make customized patient-derived cell lines by reprogramming noninvasively retrieved somatic cells. These cell lines have the potential to faithfully represent an individual's genetic background; therefore, in the absence of available human brain tissue from a living patient, these models have a significant advantage relative to other models of neurodevelopmental disease. When using human induced pluripotent stem cells (hiPSCs) to model X-linked developmental disorders or inherited conditions that undergo sex-specific modulation of penetrance (e.g., autism spectrum disorders), there are significant complexities in the course and status of X chromosome inactivation (XCI) that are crucial to consider in establishing the validity of cellular models. There are major gaps and inconsistencies in the existing literature regarding XCI status during the derivation and maintenance of hiPSCs and their differentiation into neurons. Here, we briefly describe the importance of the problem, review the findings and inconsistencies of the existing literature, delineate options for specifying XCI status in clonal populations, and develop recommendations for future studies. En ligne : http://dx.doi.org/10.1186/s11689-016-9155-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348
in Journal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.22[article] Complexities of X chromosome inactivation status in female human induced pluripotent stem cells-a brief review and scientific update for autism research [Texte imprimé et/ou numérique] / M. G. DANDULAKIS, Auteur ; K. MEGANATHAN, Auteur ; K. L. KROLL, Auteur ; A. BONNI, Auteur ; John N. CONSTANTINO, Auteur . - p.22.
Langues : Anglais (eng)
in Journal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.22
Mots-clés : Asd Autism Developmental disorders X chromosome X-inactivation X-linked ASD X-reactivation iPSC "Female protective effect" Index. décimale : PER Périodiques Résumé : Induced pluripotent stem cells (iPSCs) allow researchers to make customized patient-derived cell lines by reprogramming noninvasively retrieved somatic cells. These cell lines have the potential to faithfully represent an individual's genetic background; therefore, in the absence of available human brain tissue from a living patient, these models have a significant advantage relative to other models of neurodevelopmental disease. When using human induced pluripotent stem cells (hiPSCs) to model X-linked developmental disorders or inherited conditions that undergo sex-specific modulation of penetrance (e.g., autism spectrum disorders), there are significant complexities in the course and status of X chromosome inactivation (XCI) that are crucial to consider in establishing the validity of cellular models. There are major gaps and inconsistencies in the existing literature regarding XCI status during the derivation and maintenance of hiPSCs and their differentiation into neurons. Here, we briefly describe the importance of the problem, review the findings and inconsistencies of the existing literature, delineate options for specifying XCI status in clonal populations, and develop recommendations for future studies. En ligne : http://dx.doi.org/10.1186/s11689-016-9155-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348 Using human pluripotent stem cell models to study autism in the era of big data / Ralda NEHME in Molecular Autism, 11 (2020)
[article]
Titre : Using human pluripotent stem cell models to study autism in the era of big data Type de document : Texte imprimé et/ou numérique Auteurs : Ralda NEHME, Auteur ; Lindy E. BARRETT, Auteur Article en page(s) : 21 p. Langues : Anglais (eng) Mots-clés : Differentiation esc Human brain In vivo Regulatory policy Sample size Variance hPSC iPSC Index. décimale : PER Périodiques Résumé : Advances in human pluripotent stem cell (hPSC) biology coupled with protocols to generate diverse brain cell types in vitro have provided neuroscientists with opportunities to dissect basic and disease mechanisms in increasingly relevant cellular substrates. At the same time, large data collections and analyses have facilitated unprecedented insights into autism genetics, normal human genetic variation, and the molecular landscape of the developing human brain. While such insights have enabled the investigation of key mechanistic questions in autism, they also highlight important limitations associated with the use of existing hPSC models. In this review, we discuss four such issues which influence the efficacy of hPSC models for studying autism, including (i) sources of variance, (ii) scale and format of study design, (iii) divergence from the human brain in vivo, and (iv) regulatory policies and compliance governing the use of hPSCs. Moreover, we advocate for a set of immediate and long-term priorities to address these issues and to accelerate the generation and reproducibility of data in order to facilitate future fundamental as well as therapeutic discoveries. En ligne : http://dx.doi.org/10.1186/s13229-020-00322-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427
in Molecular Autism > 11 (2020) . - 21 p.[article] Using human pluripotent stem cell models to study autism in the era of big data [Texte imprimé et/ou numérique] / Ralda NEHME, Auteur ; Lindy E. BARRETT, Auteur . - 21 p.
Langues : Anglais (eng)
in Molecular Autism > 11 (2020) . - 21 p.
Mots-clés : Differentiation esc Human brain In vivo Regulatory policy Sample size Variance hPSC iPSC Index. décimale : PER Périodiques Résumé : Advances in human pluripotent stem cell (hPSC) biology coupled with protocols to generate diverse brain cell types in vitro have provided neuroscientists with opportunities to dissect basic and disease mechanisms in increasingly relevant cellular substrates. At the same time, large data collections and analyses have facilitated unprecedented insights into autism genetics, normal human genetic variation, and the molecular landscape of the developing human brain. While such insights have enabled the investigation of key mechanistic questions in autism, they also highlight important limitations associated with the use of existing hPSC models. In this review, we discuss four such issues which influence the efficacy of hPSC models for studying autism, including (i) sources of variance, (ii) scale and format of study design, (iii) divergence from the human brain in vivo, and (iv) regulatory policies and compliance governing the use of hPSCs. Moreover, we advocate for a set of immediate and long-term priorities to address these issues and to accelerate the generation and reproducibility of data in order to facilitate future fundamental as well as therapeutic discoveries. En ligne : http://dx.doi.org/10.1186/s13229-020-00322-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427