Increased expression of the PI3K catalytic subunit p110delta underlies elevated S6 phosphorylation and protein synthesis in an individual with autism from a multiplex family / A. 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 et/ou numérique Auteurs : A. C. POOPAL, Auteur ; L. M. SCHROEDER, Auteur ; P. S. HORN, Auteur ; Gary J. BASSELL, Auteur ; C. 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 et/ou numérique] / A. C. POOPAL, Auteur ; L. M. SCHROEDER, Auteur ; P. S. HORN, Auteur ; Gary J. BASSELL, Auteur ; C. 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

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