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Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism / F. GEVI in Molecular Autism, 7 (2016)
[article]
Titre : Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism Type de document : Texte imprimé et/ou numérique Auteurs : F. GEVI, Auteur ; L. ZOLLA, Auteur ; S. GABRIELE, Auteur ; A. M. PERSICO, Auteur Article en page(s) : 47p. Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/complications/diagnosis/urine Biomarkers/urine Case-Control Studies Child Child, Preschool Chromatography, High Pressure Liquid Coenzyme A/urine Dysbiosis/complications/diagnosis/urine Female Humans Hydrophobic and Hydrophilic Interactions Indoleacetic Acids/urine Italy Kynurenic Acid/urine Male Melatonin/urine Metabolomics/methods Pantothenic Acid/urine Purines/urine Pyrimidines/urine Quinolinic Acid/urine Riboflavin/urine Tryptophan/urine Vitamin B 6/urine Xanthurenates/urine Autism Autism spectrum disorder Kynurenine Melatonin Metabolomics Purinergic signaling Quinolinic acid Serotonin Tryptophan Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is still diagnosed through behavioral observation, due to a lack of laboratory biomarkers, which could greatly aid clinicians in providing earlier and more reliable diagnoses. Metabolomics on human biofluids provides a sensitive tool to identify metabolite profiles potentially usable as biomarkers for ASD. Initial metabolomic studies, analyzing urines and plasma of ASD and control individuals, suggested that autistic patients may share some metabolic abnormalities, despite several inconsistencies stemming from differences in technology, ethnicity, age range, and definition of "control" status. METHODS: ASD-specific urinary metabolomic patterns were explored at an early age in 30 ASD children and 30 matched controls (age range 2-7, M:F = 22:8) using hydrophilic interaction chromatography (HILIC)-UHPLC and mass spectrometry, a highly sensitive, accurate, and unbiased approach. Metabolites were then subjected to multivariate statistical analysis and grouped by metabolic pathway. RESULTS: Urinary metabolites displaying the largest differences between young ASD and control children belonged to the tryptophan and purine metabolic pathways. Also, vitamin B6, riboflavin, phenylalanine-tyrosine-tryptophan biosynthesis, pantothenate and CoA, and pyrimidine metabolism differed significantly. ASD children preferentially transform tryptophan into xanthurenic acid and quinolinic acid (two catabolites of the kynurenine pathway), at the expense of kynurenic acid and especially of melatonin. Also, the gut microbiome contributes to altered tryptophan metabolism, yielding increased levels of indolyl 3-acetic acid and indolyl lactate. CONCLUSIONS: The metabolic pathways most distinctive of young Italian autistic children largely overlap with those found in rodent models of ASD following maternal immune activation or genetic manipulations. These results are consistent with the proposal of a purine-driven cell danger response, accompanied by overproduction of epileptogenic and excitotoxic quinolinic acid, large reductions in melatonin synthesis, and gut dysbiosis. These metabolic abnormalities could underlie several comorbidities frequently associated to ASD, such as seizures, sleep disorders, and gastrointestinal symptoms, and could contribute to autism severity. Their diagnostic sensitivity, disease-specificity, and interethnic variability will merit further investigation. En ligne : http://dx.doi.org/10.1186/s13229-016-0109-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328
in Molecular Autism > 7 (2016) . - 47p.[article] Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism [Texte imprimé et/ou numérique] / F. GEVI, Auteur ; L. ZOLLA, Auteur ; S. GABRIELE, Auteur ; A. M. PERSICO, Auteur . - 47p.
Langues : Anglais (eng)
in Molecular Autism > 7 (2016) . - 47p.
Mots-clés : Autism Spectrum Disorder/complications/diagnosis/urine Biomarkers/urine Case-Control Studies Child Child, Preschool Chromatography, High Pressure Liquid Coenzyme A/urine Dysbiosis/complications/diagnosis/urine Female Humans Hydrophobic and Hydrophilic Interactions Indoleacetic Acids/urine Italy Kynurenic Acid/urine Male Melatonin/urine Metabolomics/methods Pantothenic Acid/urine Purines/urine Pyrimidines/urine Quinolinic Acid/urine Riboflavin/urine Tryptophan/urine Vitamin B 6/urine Xanthurenates/urine Autism Autism spectrum disorder Kynurenine Melatonin Metabolomics Purinergic signaling Quinolinic acid Serotonin Tryptophan Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is still diagnosed through behavioral observation, due to a lack of laboratory biomarkers, which could greatly aid clinicians in providing earlier and more reliable diagnoses. Metabolomics on human biofluids provides a sensitive tool to identify metabolite profiles potentially usable as biomarkers for ASD. Initial metabolomic studies, analyzing urines and plasma of ASD and control individuals, suggested that autistic patients may share some metabolic abnormalities, despite several inconsistencies stemming from differences in technology, ethnicity, age range, and definition of "control" status. METHODS: ASD-specific urinary metabolomic patterns were explored at an early age in 30 ASD children and 30 matched controls (age range 2-7, M:F = 22:8) using hydrophilic interaction chromatography (HILIC)-UHPLC and mass spectrometry, a highly sensitive, accurate, and unbiased approach. Metabolites were then subjected to multivariate statistical analysis and grouped by metabolic pathway. RESULTS: Urinary metabolites displaying the largest differences between young ASD and control children belonged to the tryptophan and purine metabolic pathways. Also, vitamin B6, riboflavin, phenylalanine-tyrosine-tryptophan biosynthesis, pantothenate and CoA, and pyrimidine metabolism differed significantly. ASD children preferentially transform tryptophan into xanthurenic acid and quinolinic acid (two catabolites of the kynurenine pathway), at the expense of kynurenic acid and especially of melatonin. Also, the gut microbiome contributes to altered tryptophan metabolism, yielding increased levels of indolyl 3-acetic acid and indolyl lactate. CONCLUSIONS: The metabolic pathways most distinctive of young Italian autistic children largely overlap with those found in rodent models of ASD following maternal immune activation or genetic manipulations. These results are consistent with the proposal of a purine-driven cell danger response, accompanied by overproduction of epileptogenic and excitotoxic quinolinic acid, large reductions in melatonin synthesis, and gut dysbiosis. These metabolic abnormalities could underlie several comorbidities frequently associated to ASD, such as seizures, sleep disorders, and gastrointestinal symptoms, and could contribute to autism severity. Their diagnostic sensitivity, disease-specificity, and interethnic variability will merit further investigation. En ligne : http://dx.doi.org/10.1186/s13229-016-0109-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328 Altered kynurenine pathway metabolism in autism: Implication for immune-induced glutamatergic activity / Chai K. LIM in Autism Research, 9-6 (June 2016)
[article]
Titre : Altered kynurenine pathway metabolism in autism: Implication for immune-induced glutamatergic activity Type de document : Texte imprimé et/ou numérique 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
in Autism Research > 9-6 (June 2016) . - p.621-631[article] Altered kynurenine pathway metabolism in autism: Implication for immune-induced glutamatergic activity [Texte imprimé et/ou numérique] / 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 Loss of the Chr16p11.2 ASD candidate gene QPRT leads to aberrant neuronal differentiation in the SH-SY5Y neuronal cell model / D. HASLINGER in Molecular Autism, 9 (2018)
[article]
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 et/ou numérique Auteurs : D. HASLINGER, Auteur ; R. WALTES, Auteur ; A. YOUSAF, Auteur ; S. LINDLAR, Auteur ; I. SCHNEIDER, Auteur ; C. K. LIM, Auteur ; M. M. TSAI, Auteur ; B. K. GARVALOV, Auteur ; A. ACKER-PALMER, Auteur ; N. KREZDORN, Auteur ; B. ROTTER, Auteur ; T. ACKER, Auteur ; G. J. GUILLEMIN, Auteur ; S. FULDA, Auteur ; C. 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
in Molecular Autism > 9 (2018) . - 56p.[article] Loss of the Chr16p11.2 ASD candidate gene QPRT leads to aberrant neuronal differentiation in the SH-SY5Y neuronal cell model [Texte imprimé et/ou numérique] / D. HASLINGER, Auteur ; R. WALTES, Auteur ; A. YOUSAF, Auteur ; S. LINDLAR, Auteur ; I. SCHNEIDER, Auteur ; C. K. LIM, Auteur ; M. M. TSAI, Auteur ; B. K. GARVALOV, Auteur ; A. ACKER-PALMER, Auteur ; N. KREZDORN, Auteur ; B. ROTTER, Auteur ; T. ACKER, Auteur ; G. J. GUILLEMIN, Auteur ; S. FULDA, Auteur ; C. 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