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.
|Original language||English (US)|
|Number of pages||10|
|State||Published - Sep 1 2016|
Bibliographical noteFunding Information:
We thank Dr Mani Sahebjam (Edouard Toulouse Hospital, Marseille), Dr Claude Guinard (Valvert Hospital, Marseille) and Dr Rémy Defer (Montperrin Hospital, Aix-en-Provence) for their help in recruiting the participants in this study. We are also thankful to Claudine Rumeau for magnetic resonance imaging analyses, Kevin Baranger for providing neuronal culture as well as Stéphanie Frecourt, Rim Yamani and Rupa Devi Soligalla for technical assistance. We thank the C. elegans Gene Knockout Consortium, S Mitani and the National Bioresource Project and J Kaplan and L Bianchi for generously providing strains. Other strains used in this study were provided by the Caenorhabditis Genetics Center, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). We also thank the C. elegans TransgenOme Project and Knudra. This research was funded by Fondation de France (#2004 010855; #2004 010825; #2007 005780), CNRS and Aix-Marseille University.
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ASJC Scopus subject areas
- Molecular Biology
- Psychiatry and Mental health
- Cellular and Molecular Neuroscience