Disruption of melatonin synthesis is associated with impaired 14-3-3 and miR-451 levels in patients with autism spectrum disorders
Abstract Autism spectrum disorders (ASD) are characterized by a wide genetic and clinical heterogeneity. However, some biochemical impairments, including decreased melatonin (crucial for circadian regulation) and elevated platelet N-acetylserotonin (the precursor of melatonin) have been reported as...
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| Format: | Article |
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Nature Portfolio
2017-05-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-02152-x |
| _version_ | 1818345099022565376 |
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| author | Cécile Pagan Hany Goubran-Botros Richard Delorme Marion Benabou Nathalie Lemière Kerren Murray Frédérique Amsellem Jacques Callebert Pauline Chaste Stéphane Jamain Fabien Fauchereau Guillaume Huguet Erik Maronde Marion Leboyer Jean-Marie Launay Thomas Bourgeron |
| author_facet | Cécile Pagan Hany Goubran-Botros Richard Delorme Marion Benabou Nathalie Lemière Kerren Murray Frédérique Amsellem Jacques Callebert Pauline Chaste Stéphane Jamain Fabien Fauchereau Guillaume Huguet Erik Maronde Marion Leboyer Jean-Marie Launay Thomas Bourgeron |
| author_sort | Cécile Pagan |
| collection | DOAJ |
| description | Abstract Autism spectrum disorders (ASD) are characterized by a wide genetic and clinical heterogeneity. However, some biochemical impairments, including decreased melatonin (crucial for circadian regulation) and elevated platelet N-acetylserotonin (the precursor of melatonin) have been reported as very frequent features in individuals with ASD. To address the mechanisms of these dysfunctions, we investigated melatonin synthesis in post-mortem pineal glands - the main source of melatonin (9 patients and 22 controls) - and gut samples - the main source of serotonin (11 patients and 13 controls), and in blood platelets from 239 individuals with ASD, their first-degree relatives and 278 controls. Our results elucidate the enzymatic mechanism for melatonin deficit in ASD, involving a reduction of both enzyme activities contributing to melatonin synthesis (AANAT and ASMT), observed in the pineal gland as well as in gut and platelets of patients. Further investigations suggest new, post-translational (reduced levels of 14-3-3 proteins which regulate AANAT and ASMT activities) and post-transcriptional (increased levels of miR-451, targeting 14-3-3ζ) mechanisms to these impairments. This study thus gives insights into the pathophysiological pathways involved in ASD. |
| first_indexed | 2024-12-13T16:56:59Z |
| format | Article |
| id | doaj.art-f46cefc850c64dbfa6f36f39d8a0b82c |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-13T16:56:59Z |
| publishDate | 2017-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-f46cefc850c64dbfa6f36f39d8a0b82c2022-12-21T23:37:54ZengNature PortfolioScientific Reports2045-23222017-05-017111110.1038/s41598-017-02152-xDisruption of melatonin synthesis is associated with impaired 14-3-3 and miR-451 levels in patients with autism spectrum disordersCécile Pagan0Hany Goubran-Botros1Richard Delorme2Marion Benabou3Nathalie Lemière4Kerren Murray5Frédérique Amsellem6Jacques Callebert7Pauline Chaste8Stéphane Jamain9Fabien Fauchereau10Guillaume Huguet11Erik Maronde12Marion Leboyer13Jean-Marie Launay14Thomas Bourgeron15Institut Pasteur, Human Genetics and Cognitive Functions UnitInstitut Pasteur, Human Genetics and Cognitive Functions UnitInstitut Pasteur, Human Genetics and Cognitive Functions UnitInstitut Pasteur, Human Genetics and Cognitive Functions UnitInstitut Pasteur, Human Genetics and Cognitive Functions UnitInstitut Pasteur, Human Genetics and Cognitive Functions UnitInstitut Pasteur, Human Genetics and Cognitive Functions UnitService de Biochimie et Biologie Moléculaire, INSERM U942, Hôpital Lariboisière, APHPInstitut Pasteur, Human Genetics and Cognitive Functions UnitFondation FondaMentalInstitut Pasteur, Human Genetics and Cognitive Functions UnitInstitut Pasteur, Human Genetics and Cognitive Functions UnitInstitute for Anatomy III, Goethe-UniversitätFondation FondaMentalFondation FondaMentalInstitut Pasteur, Human Genetics and Cognitive Functions UnitAbstract Autism spectrum disorders (ASD) are characterized by a wide genetic and clinical heterogeneity. However, some biochemical impairments, including decreased melatonin (crucial for circadian regulation) and elevated platelet N-acetylserotonin (the precursor of melatonin) have been reported as very frequent features in individuals with ASD. To address the mechanisms of these dysfunctions, we investigated melatonin synthesis in post-mortem pineal glands - the main source of melatonin (9 patients and 22 controls) - and gut samples - the main source of serotonin (11 patients and 13 controls), and in blood platelets from 239 individuals with ASD, their first-degree relatives and 278 controls. Our results elucidate the enzymatic mechanism for melatonin deficit in ASD, involving a reduction of both enzyme activities contributing to melatonin synthesis (AANAT and ASMT), observed in the pineal gland as well as in gut and platelets of patients. Further investigations suggest new, post-translational (reduced levels of 14-3-3 proteins which regulate AANAT and ASMT activities) and post-transcriptional (increased levels of miR-451, targeting 14-3-3ζ) mechanisms to these impairments. This study thus gives insights into the pathophysiological pathways involved in ASD.https://doi.org/10.1038/s41598-017-02152-x |
| spellingShingle | Cécile Pagan Hany Goubran-Botros Richard Delorme Marion Benabou Nathalie Lemière Kerren Murray Frédérique Amsellem Jacques Callebert Pauline Chaste Stéphane Jamain Fabien Fauchereau Guillaume Huguet Erik Maronde Marion Leboyer Jean-Marie Launay Thomas Bourgeron Disruption of melatonin synthesis is associated with impaired 14-3-3 and miR-451 levels in patients with autism spectrum disorders Scientific Reports |
| title | Disruption of melatonin synthesis is associated with impaired 14-3-3 and miR-451 levels in patients with autism spectrum disorders |
| title_full | Disruption of melatonin synthesis is associated with impaired 14-3-3 and miR-451 levels in patients with autism spectrum disorders |
| title_fullStr | Disruption of melatonin synthesis is associated with impaired 14-3-3 and miR-451 levels in patients with autism spectrum disorders |
| title_full_unstemmed | Disruption of melatonin synthesis is associated with impaired 14-3-3 and miR-451 levels in patients with autism spectrum disorders |
| title_short | Disruption of melatonin synthesis is associated with impaired 14-3-3 and miR-451 levels in patients with autism spectrum disorders |
| title_sort | disruption of melatonin synthesis is associated with impaired 14 3 3 and mir 451 levels in patients with autism spectrum disorders |
| url | https://doi.org/10.1038/s41598-017-02152-x |
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