Identification des associations probables entre la carence de folate cérébrale et la pathogenèse métabolique et génétique complexe des troubles du spectre de l'autisme grâce à l'utilisation d'une approche pilote de modélisation des interactions

Aperçu: G.M.

Récemment, le déficit en folate cérébral (CFD) a été suggéré d'être impliqué dans la pathogenèse des troubles du spectre de l'autisme (TSA). Cependant, le rôle exact du métabolisme des folates dans la pathogenèse des TSA, l'identification des mécanismes pathogènes sous-jacents et des voies métaboliques altérées restent inexpliqués. Le but de l'étude était  d'identifier les liens entre les TSA et le métabolisme cérébral perturbé en mettant l'accent sur le métabolismae anormal du folate. 

La stratégie de modélisation utilisée a identifié des interactions déjà connues soutenues par des analyses fondées sur des preuves, mais aussi de nouvelles interactions plausibles qui pourraient être validées dans des études fonctionnelles et / ou cliniques ultérieures

Autism Res. 2017 Mar 24. doi: 10.1002/aur.1780.

Identification of likely associations between cerebral folate deficiency and complex genetic- and metabolic pathogenesis of autism spectrum disorders by utilization of a pilot interaction modeling approach

Krsička D¹, Geryk J¹, Vlčková M¹, Havlovicová M¹, Macek M Jr¹, Pourová R¹.

Author information

1

Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University and University Hospital Motol, V Úvalu 84, 150 06 Prague, Czech Republic.

Abstract

Recently, cerebral folate deficiency (CFD) was suggested to be involved in the pathogenesis of autism spectrum disorders (ASD). However, the exact role of folate metabolism in the pathogenesis of ASD, identification of underlying pathogenic mechanisms and impaired metabolic pathways remain unexplained. The aim of our study was to develop and test a novel, unbiased, bioinformatics approach in order to identify links between ASD and disturbed cerebral metabolism by focusing on abnormal folate metabolism, which could foster patient stratification and novel therapeutic interventions. An unbiased, automatable, computational workflow interaction model was developed using available data from public databases. The interaction network model of ASD-associated genes with known cerebral expression and function (SFARI) and metabolic networks (MetScape), including connections to known metabolic substrates, metabolites and cofactors involving folates, was established. Intersection of bioinformatically created networks resulted in a limited amount of interaction modules pointing to common disturbed metabolic pathways, linking ASD to CFD. Two independent interaction modules (comprising three pathways) covering enzymes encoded by ASD-related genes and folate cofactors utilizing enzymes were generated. Module 1 suggested possible interference of CFD with serine and lysine metabolism, while module 2 identified correlations with purine metabolism and inosine monophosphate production. Since our approach was primarily conceived as a proof of principle, further amendments of the presented initial model are necessary to obtain additional actionable outcomes. Our modelling strategy identified not only previously known interactions supported by evidence-based analyses, but also novel plausible interactions, which could be validated in subsequent functional and/or clinical studies. Autism Res 2017. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

© 2017 International Society for Autism Research, Wiley Periodicals, Inc.

PMID: 28339176

DOI: 10.1002/aur.1780