Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux

Type de document

ARTICLE A COMITE DE LECTURE REPERTORIE DANS BDI (ACL)

Langue

anglais

Auteur

FERON ; GEPNER ; LACASSAGNE ; STEPHAN ; MESNAGE ; BLANCHARD ; BOULANGER ; TARDIF ; DEVEZE ; ROUSSEAU ; SUZUKI ; IZPISUA BELMONTE ; KHRESTCHATISKY ; NIVET ; ERARD-GARCIA

Résumé / Abstract

With an onset under the age of 3 years, autism spectrum disorders (ASDs) are now understood as diseases arising from pre- and/or early postnatal brain developmental anomalies and/or early brain insults. To unveil the molecular mechanisms taking place during the misshaping of the developing brain, we chose to study cells that are representative of the very early stages of ontogenesis, namely stem cells. Here we report on MOlybdenum COfactor Sulfurase (MOCOS), an enzyme involved in purine metabolism, as a newly identified player in ASD. We found in adult nasal olfactory stem cells of 11 adults with ASD that MOCOS is downregulated in most of them when compared with 11 age- and gender-matched control adults without any neuropsychiatric disorders. Genetic approaches using in vivo and in vitro engineered models converge to indicate that altered expression of MOCOS results in neurotransmission and synaptic defects. Furthermore, we found that MOCOS misexpression induces increased oxidative-stress sensitivity. Our results demonstrate that altered MOCOS expression is likely to have an impact on neurodevelopment and neurotransmission, and may explain comorbid conditions, including gastrointestinal disorders. We anticipate our discovery to be a fresh starting point for the study on the roles of MOCOS in brain development and its functional implications in ASD clinical symptoms. Moreover, our study suggests the possible development of new diagnostic tests based on MOCOS expression, and paves the way for drug screening targeting MOCOS and/or the purine metabolism to ultimately develop novel treatments in ASD.

Source

Molecular Psychiatry, num. 9, pp. 1215-1224 p.

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