3 recherche sur le mot-clé 'Phosphorylation'

Increased expression of the PI3K catalytic subunit p110delta underlies elevated S6 phosphorylation and protein synthesis in an individual with autism from a multiplex family / Ashwini C. POOPAL in Molecular Autism, 7 (2016)  

Public ISBD [article]  inMolecular Autism > 7 (2016) . - 3p. Titre : Increased expression of the PI3K catalytic subunit p110delta underlies elevated S6 phosphorylation and protein synthesis in an individual with autism from a multiplex family Type de document : texte imprimé Auteurs : Ashwini C. POOPAL, Auteur ; Lindsay M. SCHROEDER, Auteur ; Paul S. HORN, Auteur ; Gary J. BASSELL, Auteur ; Christina GROSS, Auteur Article en page(s) : 3p. Langues : Anglais (eng) Mots-clés : Adenine/analogs & derivatives/pharmacology  Autistic Disorder/enzymology/genetics/pathology  Biomarkers  Cell Line  Class I Phosphatidylinositol 3-Kinases/antagonists &  inhibitors/biosynthesis/genetics/physiology  Diseases in Twins  Enzyme-Linked Immunosorbent Assay  Family Health  Female  Humans  Lymphocytes/enzymology  Male  Molecular Targeted Therapy  Nerve Tissue Proteins/genetics/metabolism  Phosphorylation  Protein Processing, Post-Translational  Quinazolines/pharmacology  Ribosomal Protein S6 Kinases/metabolism  Signal Transduction/genetics  TOR Serine-Threonine Kinases/physiology  Autism  Biomarker  Ic87114  PI3K/mTOR signaling  S6 phosphorylation  p110delta Index. décimale : PER Périodiques Résumé : BACKGROUND: Dysfunctions in the PI3K/mTOR pathway have gained a lot of attention in autism research. This was initially based on the discovery of several monogenic autism spectrum disorders with mutations or defects in PI3K/mTOR signaling components. Recent genetic studies corroborate that defective PI3K/mTOR signaling might be a shared pathomechanism in autism disorders of so far unknown etiology, but functional molecular analyses in human cells are rare. The goals of this study were to perform a functional screen of cell lines from patients with idiopathic autism for defects in PI3K/mTOR signaling, to test if further functional analyses are suitable to detect underlying molecular mechanisms, and to evaluate this approach as a biomarker tool to identify therapeutic targets. METHODS: We performed phospho-S6- and S6-specific ELISA experiments on 21 lymphoblastoid cell lines from the AGRE collection and on 37 lymphoblastoid cell lines from the Simons Simplex Collection and their healthy siblings. Cell lines from one individual with increased S6 phosphorylation and his multiplex family were analyzed in further detail to identify upstream defects in PI3K signaling associated with autism diagnosis. RESULTS: We detected significantly increased S6 phosphorylation in 3 of the 21 lymphoblastoid cell lines from AGRE compared to a healthy control and in 1 of the 37 lymphoblastoid cell lines from the Simons Simplex Collection compared to the healthy sibling. Further analysis of cells from one individual with elevated S6 phosphorylation showed increased expression of the PI3K catalytic subunit p110delta, which was also observed in lymphoblastoid cells from other autistic siblings but not unaffected members in his multiplex family. The p110delta-selective inhibitor IC87114 reduced elevated S6 phosphorylation and protein synthesis in this cell line. CONCLUSIONS: Our results suggest that functional analysis of PI3K/mTOR signaling is a biomarker tool to identify disease-associated molecular defects that could serve as therapeutic targets in autism. Using this approach, we discovered impaired signaling and protein synthesis through the PI3K catalytic subunit p110delta as an underlying molecular defect and potential treatment target in select autism spectrum disorders. Increased p110delta activity was recently associated with schizophrenia, and our results suggest that p110delta may also be implicated in autism. En ligne : http://dx.doi.org/10.1186/s13229-015-0066-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 [article] Increased expression of the PI3K catalytic subunit p110delta underlies elevated S6 phosphorylation and protein synthesis in an individual with autism from a multiplex family [texte imprimé] / Ashwini C. POOPAL, Auteur ; Lindsay M. SCHROEDER, Auteur ; Paul S. HORN, Auteur ; Gary J. BASSELL, Auteur ; Christina GROSS, Auteur . - 3p. Langues : Anglais (eng) in Molecular Autism > 7 (2016) . - 3p. Mots-clés : Adenine/analogs & derivatives/pharmacology  Autistic Disorder/enzymology/genetics/pathology  Biomarkers  Cell Line  Class I Phosphatidylinositol 3-Kinases/antagonists &  inhibitors/biosynthesis/genetics/physiology  Diseases in Twins  Enzyme-Linked Immunosorbent Assay  Family Health  Female  Humans  Lymphocytes/enzymology  Male  Molecular Targeted Therapy  Nerve Tissue Proteins/genetics/metabolism  Phosphorylation  Protein Processing, Post-Translational  Quinazolines/pharmacology  Ribosomal Protein S6 Kinases/metabolism  Signal Transduction/genetics  TOR Serine-Threonine Kinases/physiology  Autism  Biomarker  Ic87114  PI3K/mTOR signaling  S6 phosphorylation  p110delta Index. décimale : PER Périodiques Résumé : BACKGROUND: Dysfunctions in the PI3K/mTOR pathway have gained a lot of attention in autism research. This was initially based on the discovery of several monogenic autism spectrum disorders with mutations or defects in PI3K/mTOR signaling components. Recent genetic studies corroborate that defective PI3K/mTOR signaling might be a shared pathomechanism in autism disorders of so far unknown etiology, but functional molecular analyses in human cells are rare. The goals of this study were to perform a functional screen of cell lines from patients with idiopathic autism for defects in PI3K/mTOR signaling, to test if further functional analyses are suitable to detect underlying molecular mechanisms, and to evaluate this approach as a biomarker tool to identify therapeutic targets. METHODS: We performed phospho-S6- and S6-specific ELISA experiments on 21 lymphoblastoid cell lines from the AGRE collection and on 37 lymphoblastoid cell lines from the Simons Simplex Collection and their healthy siblings. Cell lines from one individual with increased S6 phosphorylation and his multiplex family were analyzed in further detail to identify upstream defects in PI3K signaling associated with autism diagnosis. RESULTS: We detected significantly increased S6 phosphorylation in 3 of the 21 lymphoblastoid cell lines from AGRE compared to a healthy control and in 1 of the 37 lymphoblastoid cell lines from the Simons Simplex Collection compared to the healthy sibling. Further analysis of cells from one individual with elevated S6 phosphorylation showed increased expression of the PI3K catalytic subunit p110delta, which was also observed in lymphoblastoid cells from other autistic siblings but not unaffected members in his multiplex family. The p110delta-selective inhibitor IC87114 reduced elevated S6 phosphorylation and protein synthesis in this cell line. CONCLUSIONS: Our results suggest that functional analysis of PI3K/mTOR signaling is a biomarker tool to identify disease-associated molecular defects that could serve as therapeutic targets in autism. Using this approach, we discovered impaired signaling and protein synthesis through the PI3K catalytic subunit p110delta as an underlying molecular defect and potential treatment target in select autism spectrum disorders. Increased p110delta activity was recently associated with schizophrenia, and our results suggest that p110delta may also be implicated in autism. En ligne : http://dx.doi.org/10.1186/s13229-015-0066-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329

Effects of sex and DTNBP1 (dysbindin) null gene mutation on the developmental GluN2B-GluN2A switch in the mouse cortex and hippocampus / Duncan SINCLAIR in Journal of Neurodevelopmental Disorders, 8-1 (December 2016)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.14 Titre : Effects of sex and DTNBP1 (dysbindin) null gene mutation on the developmental GluN2B-GluN2A switch in the mouse cortex and hippocampus Type de document : texte imprimé Auteurs : Duncan SINCLAIR, Auteur ; Joseph CESARE, Auteur ; Mary MCMULLEN, Auteur ; Greg C. CARLSON, Auteur ; Chang-Gyu HAHN, Auteur ; Karin E. BORGMANN-WINTER, Auteur Article en page(s) : p.14 Langues : Anglais (eng) Mots-clés : Cortex  Dtnbp1  Development  Dysbindin  GluN2B  Hippocampus  Nmda  Phosphorylation  Postsynaptic density  Sex difference Index. décimale : PER Périodiques Résumé : BACKGROUND: Neurodevelopmental disorders such as autism spectrum disorders and schizophrenia differentially impact males and females and are highly heritable. The ways in which sex and genetic vulnerability influence the pathogenesis of these disorders are not clearly understood. The n-methyl-d-aspartate (NMDA) receptor pathway has been implicated in schizophrenia and autism spectrum disorders and changes dramatically across postnatal development at the level of the GluN2B-GluN2A subunit "switch" (a shift from reliance on GluN2B-containing receptors to reliance on GluN2A-containing receptors). We investigated whether sex and genetic vulnerability (specifically, null mutation of DTNBP1 [dysbindin; a possible susceptibility gene for schizophrenia]) influence the developmental GluN2B-GluN2A switch. METHODS: Subcellular fractionation to enrich for postsynaptic density (PSD), together with Western blotting and kinase assay, were used to investigate the GluN2B-GluN2A switch in the cortex and hippocampus of male and female DTNBP1 null mutant mice and their wild-type littermates. Main effects of sex and DTNBP1 genotype, and interactions with age, were assessed using factorial ANOVA. RESULTS: Sex differences in the GluN2B-GluN2A switch emerged across development at the frontal cortical synapse, in parameters related to GluN2B. Males across genotypes displayed higher GluN2B:GluN2A and GluN2B:GluN1 ratios (p < 0.05 and p < 0.01, respectively), higher GluN2B phosphorylation at Y1472 (p < 0.01), and greater abundance of PLCgamma (p < 0.01) and Fyn (p = 0.055) relative to females. In contrast, effects of DTNBP1 were evident exclusively in the hippocampus. The developmental trajectory of GluN2B was disrupted in DTNBP1 null mice (genotype x age interaction p < 0.05), which also displayed an increased synaptic GluN2A:GluN1 ratio (p < 0.05) and decreased PLCgamma (p < 0.05) and Fyn (only in females; p < 0.0005) compared to wild-types. CONCLUSIONS: Sex and DTNBP1 mutation influence the GluN2B-GluN2A switch at the synapse in a brain-region-specific fashion involving pY1472-GluN2B, Fyn, and PLCgamma. This highlights the possible mechanisms through which risk factors may mediate their effects on vulnerability to disorders of NMDA receptor dysfunction. En ligne : http://dx.doi.org/10.1186/s11689-016-9148-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348 [article] Effects of sex and DTNBP1 (dysbindin) null gene mutation on the developmental GluN2B-GluN2A switch in the mouse cortex and hippocampus [texte imprimé] / Duncan SINCLAIR, Auteur ; Joseph CESARE, Auteur ; Mary MCMULLEN, Auteur ; Greg C. CARLSON, Auteur ; Chang-Gyu HAHN, Auteur ; Karin E. BORGMANN-WINTER, Auteur . - p.14. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.14 Mots-clés : Cortex  Dtnbp1  Development  Dysbindin  GluN2B  Hippocampus  Nmda  Phosphorylation  Postsynaptic density  Sex difference Index. décimale : PER Périodiques Résumé : BACKGROUND: Neurodevelopmental disorders such as autism spectrum disorders and schizophrenia differentially impact males and females and are highly heritable. The ways in which sex and genetic vulnerability influence the pathogenesis of these disorders are not clearly understood. The n-methyl-d-aspartate (NMDA) receptor pathway has been implicated in schizophrenia and autism spectrum disorders and changes dramatically across postnatal development at the level of the GluN2B-GluN2A subunit "switch" (a shift from reliance on GluN2B-containing receptors to reliance on GluN2A-containing receptors). We investigated whether sex and genetic vulnerability (specifically, null mutation of DTNBP1 [dysbindin; a possible susceptibility gene for schizophrenia]) influence the developmental GluN2B-GluN2A switch. METHODS: Subcellular fractionation to enrich for postsynaptic density (PSD), together with Western blotting and kinase assay, were used to investigate the GluN2B-GluN2A switch in the cortex and hippocampus of male and female DTNBP1 null mutant mice and their wild-type littermates. Main effects of sex and DTNBP1 genotype, and interactions with age, were assessed using factorial ANOVA. RESULTS: Sex differences in the GluN2B-GluN2A switch emerged across development at the frontal cortical synapse, in parameters related to GluN2B. Males across genotypes displayed higher GluN2B:GluN2A and GluN2B:GluN1 ratios (p < 0.05 and p < 0.01, respectively), higher GluN2B phosphorylation at Y1472 (p < 0.01), and greater abundance of PLCgamma (p < 0.01) and Fyn (p = 0.055) relative to females. In contrast, effects of DTNBP1 were evident exclusively in the hippocampus. The developmental trajectory of GluN2B was disrupted in DTNBP1 null mice (genotype x age interaction p < 0.05), which also displayed an increased synaptic GluN2A:GluN1 ratio (p < 0.05) and decreased PLCgamma (p < 0.05) and Fyn (only in females; p < 0.0005) compared to wild-types. CONCLUSIONS: Sex and DTNBP1 mutation influence the GluN2B-GluN2A switch at the synapse in a brain-region-specific fashion involving pY1472-GluN2B, Fyn, and PLCgamma. This highlights the possible mechanisms through which risk factors may mediate their effects on vulnerability to disorders of NMDA receptor dysfunction. En ligne : http://dx.doi.org/10.1186/s11689-016-9148-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348

Protein Kinase A in neurological disorders / Alexander G.P. GLEBOV-MCCLOUD in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : Protein Kinase A in neurological disorders Type de document : texte imprimé Auteurs : Alexander G.P. GLEBOV-MCCLOUD, Auteur ; Walter S. SAIDE, Auteur ; Marie E. GAINE, Auteur ; Stefan STRACK, Auteur Langues : Anglais (eng) Mots-clés : Humans  Cyclic AMP-Dependent Protein Kinases/genetics/metabolism  Phosphorylation  Signal Transduction  Nervous System Diseases  Creb  Cognition  Endocrine Systems  Gene transcription  Kinases  Learning  Mapk  Memory  Metabolic Disorders  Movement Disorders  Neurodegeneration  Neurodevelopment  Pka  Protein phosphorylation  cAMP Index. décimale : PER Périodiques Résumé : Cyclic adenosine 3', 5' monophosphate (cAMP)-dependent Protein Kinase A (PKA) is a multi-functional serine/threonine kinase that regulates a wide variety of physiological processes including gene transcription, metabolism, and synaptic plasticity. Genomic sequencing studies have identified both germline and somatic variants of the catalytic and regulatory subunits of PKA in patients with metabolic and neurodevelopmental disorders. In this review we discuss the classical cAMP/PKA signaling pathway and the disease phenotypes that result from PKA variants. This review highlights distinct isoform-specific cognitive deficits that occur in both PKA catalytic and regulatory subunits, and how tissue-specific distribution of these isoforms may contribute to neurodevelopmental disorders in comparison to more generalized endocrine dysfunction. En ligne : https://dx.doi.org/10.1186/s11689-024-09525-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] Protein Kinase A in neurological disorders [texte imprimé] / Alexander G.P. GLEBOV-MCCLOUD, Auteur ; Walter S. SAIDE, Auteur ; Marie E. GAINE, Auteur ; Stefan STRACK, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Humans  Cyclic AMP-Dependent Protein Kinases/genetics/metabolism  Phosphorylation  Signal Transduction  Nervous System Diseases  Creb  Cognition  Endocrine Systems  Gene transcription  Kinases  Learning  Mapk  Memory  Metabolic Disorders  Movement Disorders  Neurodegeneration  Neurodevelopment  Pka  Protein phosphorylation  cAMP Index. décimale : PER Périodiques Résumé : Cyclic adenosine 3', 5' monophosphate (cAMP)-dependent Protein Kinase A (PKA) is a multi-functional serine/threonine kinase that regulates a wide variety of physiological processes including gene transcription, metabolism, and synaptic plasticity. Genomic sequencing studies have identified both germline and somatic variants of the catalytic and regulatory subunits of PKA in patients with metabolic and neurodevelopmental disorders. In this review we discuss the classical cAMP/PKA signaling pathway and the disease phenotypes that result from PKA variants. This review highlights distinct isoform-specific cognitive deficits that occur in both PKA catalytic and regulatory subunits, and how tissue-specific distribution of these isoforms may contribute to neurodevelopmental disorders in comparison to more generalized endocrine dysfunction. En ligne : https://dx.doi.org/10.1186/s11689-024-09525-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575