Molecular basis of Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterised by an enormous heterogeneity of biological and clinical features. Emerging evidence suggests that protein synthesis is dysregulated in ASD and in gastrointestinal disorders and that the gut microbiota might contribute to the pathogenesis of autism. The gut microbiota and the brain are connected by bidirectional network encompassing several neuronal and non-neuronal pathways, referred to microbiota-gut-brain axis. Despite the body of studies reporting impairments in mRNA translational rate and gastrointestinal problems in ASD, the molecular signature underlying Autism Spectrum Disorder remains to be elucidated. The work in this thesis revealed altered expression in children with mild and severe idiopathic autism of pathways regulating protein synthesis regulators, such as mTOR and MAPK. Furthermore, using a mouse model for a syndromic form of ASD, namely the Fragile X Syndrome, the Fmr1 KO, the microbiome composition and gastrointestinal function were studied and found altered. In the first part of the PhD work, 55 subjects were recruited, 22 of which were typically developing individuals and 33 were patients aged between 3 and 11 years, with idiopathic autism. Components of the mTOR and MAPK signalling pathways were analysed in peripheral blood of mononuclear cells at the protein level. Consequently, the molecular profiling was studied in relation to the degree of autism severity, stratifying patients according to their clinical phenotypes. The data showed an enhanced activity of the mTOR and MAPK pathways and, specifically, rpS6, p-eIF4E, TSC1 and p-MNK1 expression discriminated patients according to their clinical diagnosis. The second part of the PhD thesis focused on the gut flora composition of the Fmr1 KO compared to WT mice. The findings highlighted for the first time, impaired intestinal barrier permeability in the Fmr1 KO mice. Interestingly, the FXS microbiome landscape changes during development. Finally, shifts in the gut bacterial composition were accompanied by gastrointestinal barrier perturbations, indicating the presence of a gastrointestinal pathology in a syndromic form of ASD. Altogether, the results suggest that key players of protein synthesis signalling pathway/s might represent a molecular signature of clinical severity in ASD. In addition, we identified disruption of specific bacterial taxa that may constitute promising potential probiotic therapy for gastrointestinal disorders and behavioural symptoms associated with Autism Spectrum Disorder.