Altered kynurenine pathway metabolism in autism: Implication for immune-induced glutamatergic activity / Chai K. LIM in Autism Research, 9-6 (June 2016)  

Public ISBD [article]  inAutism Research > 9-6 (June 2016) . - p.621-631 Titre : Altered kynurenine pathway metabolism in autism: Implication for immune-induced glutamatergic activity Type de document : texte imprimé Auteurs : Chai K. LIM, Auteur ; Musthafa M. ESSA, Auteur ; Roberta DE PAULA MARTINS, Auteur ; David B. LOVEJOY, Auteur ; Ayse A. BILGIN, Auteur ; Mostafa I. WALY, Auteur ; Yahya M. AL-FARSI, Auteur ; Marwan M. AL-SHARBATI, Auteur ; Mohammed A. AL-SHAFFAE, Auteur ; Gilles J. GUILLEMIN, Auteur Article en page(s) : p.621-631 Langues : Anglais (eng) Mots-clés : kynurenine pathway  quinolinic acid  excitotoxicity  autism  neuroinflammation  glutamatergic activity Index. décimale : PER Périodiques Résumé : Dysfunction of the serotoninergic and glutamatergic systems is implicated in the pathogenesis of autism spectrum disorder (ASD) together with various neuroinflammatory mediators. As the kynurenine pathway (KP) of tryptophan degradation is activated in neuroinflammatory states, we hypothesized that there may be a link between inflammation in ASD and enhanced KP activation resulting in reduced serotonin synthesis from tryptophan and production of KP metabolites capable of modulating glutamatergic activity. A cross-sectional study of 15 different Omani families with newly diagnosed children with ASD (n = 15) and their age-matched healthy siblings (n = 12) was designed. Immunological profile and the KP metabolic signature were characterized in the study participants. Our data indicated that there were alterations to the KP in ASD. Specifically, increased production of the downstream metabolite, quinolinic acid, which is capable of enhancing glutamatergic neurotransmission was noted. Correlation studies also demonstrated that the presence of inflammation induced KP activation in ASD. Until now, previous studies have failed to establish a link between inflammation, glutamatergic activity, and the KP. Our findings also suggest that increased quinolinic acid may be linked to 16p11.2 mutations leading to abnormal glutamatergic activity associated with ASD pathogenesis and may help rationalize the efficacy of sulforaphane treatment in ASD. Autism Res 2016, 9: 621–631. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. En ligne : http://dx.doi.org/10.1002/aur.1565 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=290 [article] Altered kynurenine pathway metabolism in autism: Implication for immune-induced glutamatergic activity [texte imprimé] / Chai K. LIM, Auteur ; Musthafa M. ESSA, Auteur ; Roberta DE PAULA MARTINS, Auteur ; David B. LOVEJOY, Auteur ; Ayse A. BILGIN, Auteur ; Mostafa I. WALY, Auteur ; Yahya M. AL-FARSI, Auteur ; Marwan M. AL-SHARBATI, Auteur ; Mohammed A. AL-SHAFFAE, Auteur ; Gilles J. GUILLEMIN, Auteur . - p.621-631. Langues : Anglais (eng) in Autism Research > 9-6 (June 2016) . - p.621-631 Mots-clés : kynurenine pathway  quinolinic acid  excitotoxicity  autism  neuroinflammation  glutamatergic activity Index. décimale : PER Périodiques Résumé : Dysfunction of the serotoninergic and glutamatergic systems is implicated in the pathogenesis of autism spectrum disorder (ASD) together with various neuroinflammatory mediators. As the kynurenine pathway (KP) of tryptophan degradation is activated in neuroinflammatory states, we hypothesized that there may be a link between inflammation in ASD and enhanced KP activation resulting in reduced serotonin synthesis from tryptophan and production of KP metabolites capable of modulating glutamatergic activity. A cross-sectional study of 15 different Omani families with newly diagnosed children with ASD (n = 15) and their age-matched healthy siblings (n = 12) was designed. Immunological profile and the KP metabolic signature were characterized in the study participants. Our data indicated that there were alterations to the KP in ASD. Specifically, increased production of the downstream metabolite, quinolinic acid, which is capable of enhancing glutamatergic neurotransmission was noted. Correlation studies also demonstrated that the presence of inflammation induced KP activation in ASD. Until now, previous studies have failed to establish a link between inflammation, glutamatergic activity, and the KP. Our findings also suggest that increased quinolinic acid may be linked to 16p11.2 mutations leading to abnormal glutamatergic activity associated with ASD pathogenesis and may help rationalize the efficacy of sulforaphane treatment in ASD. Autism Res 2016, 9: 621–631. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. En ligne : http://dx.doi.org/10.1002/aur.1565 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=290

Impaired antioxidant status and reduced energy metabolism in autistic children / M.M. ESSA in Research in Autism Spectrum Disorders, 7-5 (May 2013)  

Public ISBD [article]  inResearch in Autism Spectrum Disorders > 7-5 (May 2013) . - p.557-565 Titre : Impaired antioxidant status and reduced energy metabolism in autistic children Type de document : texte imprimé Auteurs : M.M. ESSA, Auteur ; N. BRAIDY, Auteur ; Mostafa I. WALY, Auteur ; Yahya M. AL-FARSI, Auteur ; Marwan M. AL-SHARBATI, Auteur ; S. SUBASH, Auteur ; A. AMANAT, Auteur ; Mohammed A. AL-SHAFFAE, Auteur ; Gilles J. GUILLEMIN, Auteur Article en page(s) : p.557-565 Mots-clés : Autism  ATP  Oxidative stress  NAD+  Antioxidants Index. décimale : PER Périodiques Résumé : Accumulating evidence suggests that oxidative stress induced mechanisms are believed to be associated with the pathophysiology of autism. In this study, we recruited 19 Omani autistic children with age-matched controls to analyze their plasma and serum redox status and the levels of ATP, NAD+ and NADH using well established spectrophotometric assays. A significant decrease was observed in the levels of plasma total antioxidants (TA), reduced glutathione (GSH), superoxide and catalase activity in Omani autistic children as compared to their age-matched controls. In contrary, the level of plasma glutathione peroxidase (GSH-Px) was significantly increased in autistic children. Reduced serum NAD+ and ATP levels and lower NAD+:NADH ratio were observedin patients with autism compared to controls. Finally, a significant inverse correlation was observed between plasma GSH, SOD, catalase activity, and serum NAD+ and ATP levels, and autism severity using Childhood Autism Rating Scale (CARS) scores. The levels of plasma GSH-Px and serum NADH correlated strongly with autism severity whilst no significant correlation was observed for plasma TA. Our data suggests that increased vulnerability to oxidative stress in autism may occur as a consequence of alterations in antioxidant enzymes leading to mitochondrial dysfunction. En ligne : http://dx.doi.org/10.1016/j.rasd.2012.12.006 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=194 [article] Impaired antioxidant status and reduced energy metabolism in autistic children [texte imprimé] / M.M. ESSA, Auteur ; N. BRAIDY, Auteur ; Mostafa I. WALY, Auteur ; Yahya M. AL-FARSI, Auteur ; Marwan M. AL-SHARBATI, Auteur ; S. SUBASH, Auteur ; A. AMANAT, Auteur ; Mohammed A. AL-SHAFFAE, Auteur ; Gilles J. GUILLEMIN, Auteur . - p.557-565. in Research in Autism Spectrum Disorders > 7-5 (May 2013) . - p.557-565 Mots-clés : Autism  ATP  Oxidative stress  NAD+  Antioxidants Index. décimale : PER Périodiques Résumé : Accumulating evidence suggests that oxidative stress induced mechanisms are believed to be associated with the pathophysiology of autism. In this study, we recruited 19 Omani autistic children with age-matched controls to analyze their plasma and serum redox status and the levels of ATP, NAD+ and NADH using well established spectrophotometric assays. A significant decrease was observed in the levels of plasma total antioxidants (TA), reduced glutathione (GSH), superoxide and catalase activity in Omani autistic children as compared to their age-matched controls. In contrary, the level of plasma glutathione peroxidase (GSH-Px) was significantly increased in autistic children. Reduced serum NAD+ and ATP levels and lower NAD+:NADH ratio were observedin patients with autism compared to controls. Finally, a significant inverse correlation was observed between plasma GSH, SOD, catalase activity, and serum NAD+ and ATP levels, and autism severity using Childhood Autism Rating Scale (CARS) scores. The levels of plasma GSH-Px and serum NADH correlated strongly with autism severity whilst no significant correlation was observed for plasma TA. Our data suggests that increased vulnerability to oxidative stress in autism may occur as a consequence of alterations in antioxidant enzymes leading to mitochondrial dysfunction. En ligne : http://dx.doi.org/10.1016/j.rasd.2012.12.006 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=194

Loss of the Chr16p11.2 ASD candidate gene QPRT leads to aberrant neuronal differentiation in the SH-SY5Y neuronal cell model / Denise HASLINGER in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 56p. Titre : Loss of the Chr16p11.2 ASD candidate gene QPRT leads to aberrant neuronal differentiation in the SH-SY5Y neuronal cell model Type de document : texte imprimé Auteurs : Denise HASLINGER, Auteur ; Regina WALTES, Auteur ; Afsheen YOUSAF, Auteur ; Silvia LINDLAR, Auteur ; Isabel SCHNEIDER, Auteur ; Chai K. LIM, Auteur ; Meng-Miao TSAI, Auteur ; Boyan K. GARVALOV, Auteur ; Amparo ACKER-PALMER, Auteur ; Nicolas KREZDORN, Auteur ; Björn ROTTER, Auteur ; Till ACKER, Auteur ; Gilles J. GUILLEMIN, Auteur ; Simone FULDA, Auteur ; Christine M. FREITAG, Auteur ; Andreas G. CHIOCCHETTI, Auteur Article en page(s) : 56p. Langues : Anglais (eng) Mots-clés : 16p11.2  Autism  CRISPR/Cas9  Kynurenine  Quinolinate phosphoribosyltransferase  Quinolinic acid  Sholl analysis  has been positively reviewed by the ethic's committee Frankfurt (No 267/09).All  authors agree to publish the presented work.All authors declare that they have no  competing interests.Springer Nature remains neutral with regard to jurisdictional  claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Altered neuronal development is discussed as the underlying pathogenic mechanism of autism spectrum disorders (ASD). Copy number variations of 16p11.2 have recurrently been identified in individuals with ASD. Of the 29 genes within this region, quinolinate phosphoribosyltransferase (QPRT) showed the strongest regulation during neuronal differentiation of SH-SY5Y neuroblastoma cells. We hypothesized a causal relation between this tryptophan metabolism-related enzyme and neuronal differentiation. We thus analyzed the effect of QPRT on the differentiation of SH-SY5Y and specifically focused on neuronal morphology, metabolites of the tryptophan pathway, and the neurodevelopmental transcriptome. Methods: The gene dosage-dependent change of QPRT expression following Chr16p11.2 deletion was investigated in a lymphoblastoid cell line (LCL) of a deletion carrier and compared to his non-carrier parents. Expression of QPRT was tested for correlation with neuromorphology in SH-SY5Y cells. QPRT function was inhibited in SH-SY5Y neuroblastoma cells using (i) siRNA knockdown (KD), (ii) chemical mimicking of loss of QPRT, and (iii) complete CRISPR/Cas9-mediated knock out (KO). QPRT-KD cells underwent morphological analysis. Chemically inhibited and QPRT-KO cells were characterized using viability assays. Additionally, QPRT-KO cells underwent metabolite and whole transcriptome analyses. Genes differentially expressed upon KO of QPRT were tested for enrichment in biological processes and co-regulated gene-networks of the human brain. Results: QPRT expression was reduced in the LCL of the deletion carrier and significantly correlated with the neuritic complexity of SH-SY5Y. The reduction of QPRT altered neuronal morphology of differentiated SH-SY5Y cells. Chemical inhibition as well as complete KO of the gene were lethal upon induction of neuronal differentiation, but not proliferation. The QPRT-associated tryptophan pathway was not affected by KO. At the transcriptome level, genes linked to neurodevelopmental processes and synaptic structures were affected. Differentially regulated genes were enriched for ASD candidates, and co-regulated gene networks were implicated in the development of the dorsolateral prefrontal cortex, the hippocampus, and the amygdala. Conclusions: In this study, QPRT was causally related to in vitro neuronal differentiation of SH-SY5Y cells and affected the regulation of genes and gene networks previously implicated in ASD. Thus, our data suggest that QPRT may play an important role in the pathogenesis of ASD in Chr16p11.2 deletion carriers. En ligne : https://dx.doi.org/10.1186/s13229-018-0239-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Loss of the Chr16p11.2 ASD candidate gene QPRT leads to aberrant neuronal differentiation in the SH-SY5Y neuronal cell model [texte imprimé] / Denise HASLINGER, Auteur ; Regina WALTES, Auteur ; Afsheen YOUSAF, Auteur ; Silvia LINDLAR, Auteur ; Isabel SCHNEIDER, Auteur ; Chai K. LIM, Auteur ; Meng-Miao TSAI, Auteur ; Boyan K. GARVALOV, Auteur ; Amparo ACKER-PALMER, Auteur ; Nicolas KREZDORN, Auteur ; Björn ROTTER, Auteur ; Till ACKER, Auteur ; Gilles J. GUILLEMIN, Auteur ; Simone FULDA, Auteur ; Christine M. FREITAG, Auteur ; Andreas G. CHIOCCHETTI, Auteur . - 56p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 56p. Mots-clés : 16p11.2  Autism  CRISPR/Cas9  Kynurenine  Quinolinate phosphoribosyltransferase  Quinolinic acid  Sholl analysis  has been positively reviewed by the ethic's committee Frankfurt (No 267/09).All  authors agree to publish the presented work.All authors declare that they have no  competing interests.Springer Nature remains neutral with regard to jurisdictional  claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Altered neuronal development is discussed as the underlying pathogenic mechanism of autism spectrum disorders (ASD). Copy number variations of 16p11.2 have recurrently been identified in individuals with ASD. Of the 29 genes within this region, quinolinate phosphoribosyltransferase (QPRT) showed the strongest regulation during neuronal differentiation of SH-SY5Y neuroblastoma cells. We hypothesized a causal relation between this tryptophan metabolism-related enzyme and neuronal differentiation. We thus analyzed the effect of QPRT on the differentiation of SH-SY5Y and specifically focused on neuronal morphology, metabolites of the tryptophan pathway, and the neurodevelopmental transcriptome. Methods: The gene dosage-dependent change of QPRT expression following Chr16p11.2 deletion was investigated in a lymphoblastoid cell line (LCL) of a deletion carrier and compared to his non-carrier parents. Expression of QPRT was tested for correlation with neuromorphology in SH-SY5Y cells. QPRT function was inhibited in SH-SY5Y neuroblastoma cells using (i) siRNA knockdown (KD), (ii) chemical mimicking of loss of QPRT, and (iii) complete CRISPR/Cas9-mediated knock out (KO). QPRT-KD cells underwent morphological analysis. Chemically inhibited and QPRT-KO cells were characterized using viability assays. Additionally, QPRT-KO cells underwent metabolite and whole transcriptome analyses. Genes differentially expressed upon KO of QPRT were tested for enrichment in biological processes and co-regulated gene-networks of the human brain. Results: QPRT expression was reduced in the LCL of the deletion carrier and significantly correlated with the neuritic complexity of SH-SY5Y. The reduction of QPRT altered neuronal morphology of differentiated SH-SY5Y cells. Chemical inhibition as well as complete KO of the gene were lethal upon induction of neuronal differentiation, but not proliferation. The QPRT-associated tryptophan pathway was not affected by KO. At the transcriptome level, genes linked to neurodevelopmental processes and synaptic structures were affected. Differentially regulated genes were enriched for ASD candidates, and co-regulated gene networks were implicated in the development of the dorsolateral prefrontal cortex, the hippocampus, and the amygdala. Conclusions: In this study, QPRT was causally related to in vitro neuronal differentiation of SH-SY5Y cells and affected the regulation of genes and gene networks previously implicated in ASD. Thus, our data suggest that QPRT may play an important role in the pathogenesis of ASD in Chr16p11.2 deletion carriers. En ligne : https://dx.doi.org/10.1186/s13229-018-0239-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

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