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Auteur Adrian J. HARWOOD |
Documents disponibles écrits par cet auteur (2)
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Copy number variants (CNVs): a powerful tool for iPSC-based modelling of ASD / Danijela DRAKULIC in Molecular Autism, 11 (2020)
[article]
Titre : Copy number variants (CNVs): a powerful tool for iPSC-based modelling of ASD Type de document : Texte imprimé et/ou numérique Auteurs : Danijela DRAKULIC, Auteur ; Srdjan DJUROVIC, Auteur ; Yasir Ahmed SYED, Auteur ; Sebastiano TRATTARO, Auteur ; Nicolò CAPORALE, Auteur ; Anna FALK, Auteur ; Rivka OFIR, Auteur ; Vivi M. HEINE, Auteur ; Samuel J. R. A. CHAWNER, Auteur ; Antonio RODRIGUEZ-MORENO, Auteur ; Marianne B. M. VAN DEN BREE, Auteur ; Giuseppe TESTA, Auteur ; Spyros PETRAKIS, Auteur ; Adrian J. HARWOOD, Auteur Article en page(s) : 42 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorders (ASD) Copy number variants (CNVs) Human iPSCs Neurodevelopmental disorders (NDD) Index. décimale : PER Périodiques Résumé : Patients diagnosed with chromosome microdeletions or duplications, known as copy number variants (CNVs), present a unique opportunity to investigate the relationship between patient genotype and cell phenotype. CNVs have high genetic penetrance and give a good correlation between gene locus and patient clinical phenotype. This is especially effective for the study of patients with neurodevelopmental disorders (NDD), including those falling within the autism spectrum disorders (ASD). A key question is whether this correlation between genetics and clinical presentation at the level of the patient can be translated to the cell phenotypes arising from the neurodevelopment of patient induced pluripotent stem cells (iPSCs).Here, we examine how iPSCs derived from ASD patients with an associated CNV inform our understanding of the genetic and biological mechanisms underlying the aetiology of ASD. We consider selection of genetically characterised patient iPSCs; use of appropriate control lines; aspects of human neurocellular biology that can capture in vitro the patient clinical phenotype; and current limitations of patient iPSC-based studies. Finally, we consider how future research may be enhanced to maximise the utility of CNV patients for research of pathological mechanisms or therapeutic targets. En ligne : http://dx.doi.org/10.1186/s13229-020-00343-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427
in Molecular Autism > 11 (2020) . - 42 p.[article] Copy number variants (CNVs): a powerful tool for iPSC-based modelling of ASD [Texte imprimé et/ou numérique] / Danijela DRAKULIC, Auteur ; Srdjan DJUROVIC, Auteur ; Yasir Ahmed SYED, Auteur ; Sebastiano TRATTARO, Auteur ; Nicolò CAPORALE, Auteur ; Anna FALK, Auteur ; Rivka OFIR, Auteur ; Vivi M. HEINE, Auteur ; Samuel J. R. A. CHAWNER, Auteur ; Antonio RODRIGUEZ-MORENO, Auteur ; Marianne B. M. VAN DEN BREE, Auteur ; Giuseppe TESTA, Auteur ; Spyros PETRAKIS, Auteur ; Adrian J. HARWOOD, Auteur . - 42 p.
Langues : Anglais (eng)
in Molecular Autism > 11 (2020) . - 42 p.
Mots-clés : Autism spectrum disorders (ASD) Copy number variants (CNVs) Human iPSCs Neurodevelopmental disorders (NDD) Index. décimale : PER Périodiques Résumé : Patients diagnosed with chromosome microdeletions or duplications, known as copy number variants (CNVs), present a unique opportunity to investigate the relationship between patient genotype and cell phenotype. CNVs have high genetic penetrance and give a good correlation between gene locus and patient clinical phenotype. This is especially effective for the study of patients with neurodevelopmental disorders (NDD), including those falling within the autism spectrum disorders (ASD). A key question is whether this correlation between genetics and clinical presentation at the level of the patient can be translated to the cell phenotypes arising from the neurodevelopment of patient induced pluripotent stem cells (iPSCs).Here, we examine how iPSCs derived from ASD patients with an associated CNV inform our understanding of the genetic and biological mechanisms underlying the aetiology of ASD. We consider selection of genetically characterised patient iPSCs; use of appropriate control lines; aspects of human neurocellular biology that can capture in vitro the patient clinical phenotype; and current limitations of patient iPSC-based studies. Finally, we consider how future research may be enhanced to maximise the utility of CNV patients for research of pathological mechanisms or therapeutic targets. En ligne : http://dx.doi.org/10.1186/s13229-020-00343-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 Pharmacological intervention to restore connectivity deficits of neuronal networks derived from ASD patient iPSC with a TSC2 mutation / Mouhamed ALSAQATI in Molecular Autism, 11 (2020)
[article]
Titre : Pharmacological intervention to restore connectivity deficits of neuronal networks derived from ASD patient iPSC with a TSC2 mutation Type de document : Texte imprimé et/ou numérique Auteurs : Mouhamed ALSAQATI, Auteur ; Vivi M. HEINE, Auteur ; Adrian J. HARWOOD, Auteur Article en page(s) : 80 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is a rare genetic multisystemic disorder resulting from autosomal dominant mutations in the TSC1 or TSC2 genes. It is characterised by hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway and has severe neurodevelopmental and neurological components including autism, intellectual disability and epilepsy. In human and rodent models, loss of the TSC proteins causes neuronal hyperexcitability and synaptic dysfunction, although the consequences of these changes for the developing central nervous system are currently unclear. METHODS: Here we apply multi-electrode array-based assays to study the effects of TSC2 loss on neuronal network activity using autism spectrum disorder (ASD) patient-derived iPSCs. We examine both temporal synchronisation of neuronal bursting and spatial connectivity between electrodes across the network. RESULTS: We find that ASD patient-derived neurons with a functional loss of TSC2, in addition to possessing neuronal hyperactivity, develop a dysfunctional neuronal network with reduced synchronisation of neuronal bursting and lower spatial connectivity. These deficits of network function are associated with elevated expression of genes for inhibitory GABA signalling and glutamate signalling, indicating a potential abnormality of synaptic inhibitory-excitatory signalling. mTORC1 activity functions within a homeostatic triad of protein kinases, mTOR, AMP-dependent protein Kinase 1 (AMPK) and Unc-51 like Autophagy Activating Kinase 1 (ULK1) that orchestrate the interplay of anabolic cell growth and catabolic autophagy while balancing energy and nutrient homeostasis. The mTOR inhibitor rapamycin suppresses neuronal hyperactivity, but does not increase synchronised network activity, whereas activation of AMPK restores some aspects of network activity. In contrast, the ULK1 activator, LYN-1604, increases the network behaviour, shortens the network burst lengths and reduces the number of uncorrelated spikes. LIMITATIONS: Although a robust and consistent phenotype is observed across multiple independent iPSC cultures, the results are based on one patient. There may be more subtle differences between patients with different TSC2 mutations or differences of polygenic background within their genomes. This may affect the severity of the network deficit or the pharmacological response between TSC2 patients. CONCLUSIONS: Our observations suggest that there is a reduction in the network connectivity of the in vitro neuronal network associated with ASD patients with TSC2 mutation, which may arise via an excitatory/inhibitory imbalance due to increased GABA-signalling at inhibitory synapses. This abnormality can be effectively suppressed via activation of ULK1. En ligne : http://dx.doi.org/10.1186/s13229-020-00391-w Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433
in Molecular Autism > 11 (2020) . - 80 p.[article] Pharmacological intervention to restore connectivity deficits of neuronal networks derived from ASD patient iPSC with a TSC2 mutation [Texte imprimé et/ou numérique] / Mouhamed ALSAQATI, Auteur ; Vivi M. HEINE, Auteur ; Adrian J. HARWOOD, Auteur . - 80 p.
Langues : Anglais (eng)
in Molecular Autism > 11 (2020) . - 80 p.
Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is a rare genetic multisystemic disorder resulting from autosomal dominant mutations in the TSC1 or TSC2 genes. It is characterised by hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway and has severe neurodevelopmental and neurological components including autism, intellectual disability and epilepsy. In human and rodent models, loss of the TSC proteins causes neuronal hyperexcitability and synaptic dysfunction, although the consequences of these changes for the developing central nervous system are currently unclear. METHODS: Here we apply multi-electrode array-based assays to study the effects of TSC2 loss on neuronal network activity using autism spectrum disorder (ASD) patient-derived iPSCs. We examine both temporal synchronisation of neuronal bursting and spatial connectivity between electrodes across the network. RESULTS: We find that ASD patient-derived neurons with a functional loss of TSC2, in addition to possessing neuronal hyperactivity, develop a dysfunctional neuronal network with reduced synchronisation of neuronal bursting and lower spatial connectivity. These deficits of network function are associated with elevated expression of genes for inhibitory GABA signalling and glutamate signalling, indicating a potential abnormality of synaptic inhibitory-excitatory signalling. mTORC1 activity functions within a homeostatic triad of protein kinases, mTOR, AMP-dependent protein Kinase 1 (AMPK) and Unc-51 like Autophagy Activating Kinase 1 (ULK1) that orchestrate the interplay of anabolic cell growth and catabolic autophagy while balancing energy and nutrient homeostasis. The mTOR inhibitor rapamycin suppresses neuronal hyperactivity, but does not increase synchronised network activity, whereas activation of AMPK restores some aspects of network activity. In contrast, the ULK1 activator, LYN-1604, increases the network behaviour, shortens the network burst lengths and reduces the number of uncorrelated spikes. LIMITATIONS: Although a robust and consistent phenotype is observed across multiple independent iPSC cultures, the results are based on one patient. There may be more subtle differences between patients with different TSC2 mutations or differences of polygenic background within their genomes. This may affect the severity of the network deficit or the pharmacological response between TSC2 patients. CONCLUSIONS: Our observations suggest that there is a reduction in the network connectivity of the in vitro neuronal network associated with ASD patients with TSC2 mutation, which may arise via an excitatory/inhibitory imbalance due to increased GABA-signalling at inhibitory synapses. This abnormality can be effectively suppressed via activation of ULK1. En ligne : http://dx.doi.org/10.1186/s13229-020-00391-w Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433