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Human Inducible Pluripotent Stem Cells and Autism Spectrum Disorder: Emerging Technologies / Andre W. PHILLIPS ; Elena ARTIMOVICH ; Jonathan E. NESTOR ; John P. HUSSMAN ; Gene J. BLATT in Autism Research, 9-5 (May 2016)
[article]
Titre : Human Inducible Pluripotent Stem Cells and Autism Spectrum Disorder: Emerging Technologies Type de document : Texte imprimé et/ou numérique Auteurs : Andre W. PHILLIPS, Auteur ; Elena ARTIMOVICH, Auteur ; Jonathan E. NESTOR, Auteur ; John P. HUSSMAN, Auteur ; Gene J. BLATT, Auteur Article en page(s) : p.513-535 Langues : Anglais (eng) Mots-clés : human stem cells autism drug-screening high-throughput inducible pluripotent stem cells CRISPR optogenetics organoids Index. décimale : PER Périodiques Résumé : Autism Spectrum Disorder (ASD) is a behaviorally defined neurodevelopmental condition. Symptoms of ASD cover the spectrum from mild qualitative differences in social interaction to severe communication and social and behavioral challenges that require lifelong support. Attempts at understanding the pathophysiology of ASD have been hampered by a multifactorial etiology that stretches the limits of current behavioral and cell based models. Recent progress has implicated numerous autism-risk genes but efforts to gain a better understanding of the underlying biological mechanisms have seen slow progress. This is in part due to lack of appropriate models for complete molecular and pharmacological studies. The advent of induced pluripotent stem cells (iPSC) has reinvigorated efforts to establish more complete model systems that more reliably identify molecular pathways and predict effective drug targets and candidates in ASD. iPSCs are particularly appealing because they can be derived from human patients and controls for research purposes and provide a technology for the development of a personalized treatment regimen for ASD patients. The pluripotency of iPSCs allow them to be reprogrammed into a number of CNS cell types and phenotypically screened across many patients. This quality is already being exploited in protocols to generate 2-dimensional (2-D) and three-dimensional (3-D) models of neurons and developing brain structures. iPSC models make powerful platforms that can be interrogated using electrophysiology, gene expression studies, and other cell-based quantitative assays. iPSC technology has limitations but when combined with other model systems has great potential for helping define the underlying pathophysiology of ASD. En ligne : http://dx.doi.org/10.1002/aur.1570 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=289
in Autism Research > 9-5 (May 2016) . - p.513-535[article] Human Inducible Pluripotent Stem Cells and Autism Spectrum Disorder: Emerging Technologies [Texte imprimé et/ou numérique] / Andre W. PHILLIPS, Auteur ; Elena ARTIMOVICH, Auteur ; Jonathan E. NESTOR, Auteur ; John P. HUSSMAN, Auteur ; Gene J. BLATT, Auteur . - p.513-535.
Langues : Anglais (eng)
in Autism Research > 9-5 (May 2016) . - p.513-535
Mots-clés : human stem cells autism drug-screening high-throughput inducible pluripotent stem cells CRISPR optogenetics organoids Index. décimale : PER Périodiques Résumé : Autism Spectrum Disorder (ASD) is a behaviorally defined neurodevelopmental condition. Symptoms of ASD cover the spectrum from mild qualitative differences in social interaction to severe communication and social and behavioral challenges that require lifelong support. Attempts at understanding the pathophysiology of ASD have been hampered by a multifactorial etiology that stretches the limits of current behavioral and cell based models. Recent progress has implicated numerous autism-risk genes but efforts to gain a better understanding of the underlying biological mechanisms have seen slow progress. This is in part due to lack of appropriate models for complete molecular and pharmacological studies. The advent of induced pluripotent stem cells (iPSC) has reinvigorated efforts to establish more complete model systems that more reliably identify molecular pathways and predict effective drug targets and candidates in ASD. iPSCs are particularly appealing because they can be derived from human patients and controls for research purposes and provide a technology for the development of a personalized treatment regimen for ASD patients. The pluripotency of iPSCs allow them to be reprogrammed into a number of CNS cell types and phenotypically screened across many patients. This quality is already being exploited in protocols to generate 2-dimensional (2-D) and three-dimensional (3-D) models of neurons and developing brain structures. iPSC models make powerful platforms that can be interrogated using electrophysiology, gene expression studies, and other cell-based quantitative assays. iPSC technology has limitations but when combined with other model systems has great potential for helping define the underlying pathophysiology of ASD. En ligne : http://dx.doi.org/10.1002/aur.1570 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=289 Elevated de novo protein synthesis in FMRP-deficient human neurons and its correction by metformin treatment / Kagistia Hana UTAMI in Molecular Autism, 11 (2020)
[article]
Titre : Elevated de novo protein synthesis in FMRP-deficient human neurons and its correction by metformin treatment Type de document : Texte imprimé et/ou numérique Auteurs : Kagistia Hana UTAMI, Auteur ; Nur Amirah Binte Mohammad YUSOF, Auteur ; Jing Eugene KWA, Auteur ; Ulla-Kaisa PETERI, Auteur ; Maija L. CASTRÉN, Auteur ; Mahmoud A. POULADI, Auteur Article en page(s) : 41 p. Langues : Anglais (eng) Mots-clés : Fragile X syndrome Human stem cells Protein synthesis Therapy interest. Index. décimale : PER Périodiques Résumé : FXS is the most common genetic cause of intellectual (ID) and autism spectrum disorders (ASD). FXS is caused by loss of FMRP, an RNA-binding protein involved in the translational regulation of a large number of neuronal mRNAs. Absence of FMRP has been shown to lead to elevated protein synthesis and is thought to be a major cause of the synaptic plasticity and behavioural deficits in FXS. The increase in protein synthesis results in part from abnormal activation of key protein translation pathways downstream of ERK1/2 and mTOR signalling. Pharmacological and genetic interventions that attenuate hyperactivation of these pathways can normalize levels of protein synthesis and improve phenotypic outcomes in animal models of FXS. Several efforts are currently underway to trial this strategy in patients with FXS. To date, elevated global protein synthesis as a result of FMRP loss has not been validated in the context of human neurons. Here, using an isogenic human stem cell-based model, we show that de novo protein synthesis is elevated in FMRP-deficient neural cells. We further show that this increase is associated with elevated ERK1/2 and Akt signalling and can be rescued by metformin treatment. Finally, we examined the effect of normalizing protein synthesis on phenotypic abnormalities in FMRP-deficient neural cells. We find that treatment with metformin attenuates the increase in proliferation of FMRP-deficient neural progenitor cells but not the neuronal deficits in neurite outgrowth. The elevated level of protein synthesis and the normalization of neural progenitor proliferation by metformin treatment were validated in additional control and FXS patient-derived hiPSC lines. Overall, our results validate that loss of FMRP results in elevated de novo protein synthesis in human neurons and suggest that approaches targeting this abnormality are likely to be of partial therapeutic benefit in FXS. En ligne : http://dx.doi.org/10.1186/s13229-020-00350-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427
in Molecular Autism > 11 (2020) . - 41 p.[article] Elevated de novo protein synthesis in FMRP-deficient human neurons and its correction by metformin treatment [Texte imprimé et/ou numérique] / Kagistia Hana UTAMI, Auteur ; Nur Amirah Binte Mohammad YUSOF, Auteur ; Jing Eugene KWA, Auteur ; Ulla-Kaisa PETERI, Auteur ; Maija L. CASTRÉN, Auteur ; Mahmoud A. POULADI, Auteur . - 41 p.
Langues : Anglais (eng)
in Molecular Autism > 11 (2020) . - 41 p.
Mots-clés : Fragile X syndrome Human stem cells Protein synthesis Therapy interest. Index. décimale : PER Périodiques Résumé : FXS is the most common genetic cause of intellectual (ID) and autism spectrum disorders (ASD). FXS is caused by loss of FMRP, an RNA-binding protein involved in the translational regulation of a large number of neuronal mRNAs. Absence of FMRP has been shown to lead to elevated protein synthesis and is thought to be a major cause of the synaptic plasticity and behavioural deficits in FXS. The increase in protein synthesis results in part from abnormal activation of key protein translation pathways downstream of ERK1/2 and mTOR signalling. Pharmacological and genetic interventions that attenuate hyperactivation of these pathways can normalize levels of protein synthesis and improve phenotypic outcomes in animal models of FXS. Several efforts are currently underway to trial this strategy in patients with FXS. To date, elevated global protein synthesis as a result of FMRP loss has not been validated in the context of human neurons. Here, using an isogenic human stem cell-based model, we show that de novo protein synthesis is elevated in FMRP-deficient neural cells. We further show that this increase is associated with elevated ERK1/2 and Akt signalling and can be rescued by metformin treatment. Finally, we examined the effect of normalizing protein synthesis on phenotypic abnormalities in FMRP-deficient neural cells. We find that treatment with metformin attenuates the increase in proliferation of FMRP-deficient neural progenitor cells but not the neuronal deficits in neurite outgrowth. The elevated level of protein synthesis and the normalization of neural progenitor proliferation by metformin treatment were validated in additional control and FXS patient-derived hiPSC lines. Overall, our results validate that loss of FMRP results in elevated de novo protein synthesis in human neurons and suggest that approaches targeting this abnormality are likely to be of partial therapeutic benefit in FXS. En ligne : http://dx.doi.org/10.1186/s13229-020-00350-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427