Contributors: Gènes, Synapses et Cognition (CNRS - UMR3571 ); Institut Pasteur Paris (IP)-Centre National de la Recherche Scientifique (CNRS); Service de biochimie et biologie moléculaire; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal APHP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR139; Hospices Civils de Lyon (HCL); Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)); Institut Pasteur Paris (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS); Fondation FondaMental Créteil; AP-HP Hôpital universitaire Robert-Debré Paris; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP); Psychiatrie Translationnelle (Equipe 15); Institut Mondor de Recherche Biomédicale (IMRB); Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Réseau de coopération scientifique en santé mentale; Fondation FondaMental Créteil -Fondation FondaMental Créteil; Goethe-Universität Frankfurt am Main; This work was supported by academic institutions (Institut Pasteur, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Assistance Publique – Hôpitaux de Paris, University Paris Diderot); academic grants: ANR (SynDivAutism) and Neuron-ERANET (EUHF-AUTISM); charity foundations: Bettencourt-Schueller foundation, Orange foundation, FondaMental foundation, Conny-Maeva foundation, Cognacq-Jay foundation.; We thank the patients and their families, and the controls who accepted to participate in this study. Some tissue used in this research was obtained from Autism BrainNet that is sponsored by the Simons Foundation, and from the Maryland Brain and Tissue Bank. The authors also acknowledge the Autism Tissue Program that was the predecessor to Autism BrainNet. The Clinical Investigation Centers of Robert-Debré and Henri Mondor Hospitals obtained and processed blood samples, the Hematology departments from both hospitals (Dr MF Hurtaud and Pr M Imbert) performed platelet counts; the Anatomopathology department of Lariboisière Hospital (Pr F Gray) performed immunohistochemistry analyses; ANR-13-SAMA-0006,SynDivAutism,Diversité Synaptique dans l'autisme(2013); ANR-10-NEUR-0003,EUHFAUTISM(2010)
نبذة مختصرة : International audience ; 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.
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