30397
Disruption of Mtor and MAPK Pathways Correlates with Severity in Idiopathic Autism
The molecular signature underlying idiopathic Autism Spectrum Disorder (ASD) remains largely unknown. Some insights have been gained through the study of syndromic forms of autism and intellectual disabilities, such as Fragile X Syndrome (FXS) and Tuberous Sclerosis (TSC), two monogenic diseases associated with mutations in genes that regulate protein synthesis and affect transmission and plasticity of synapses. Thus, it has been hypothesized that excessive synaptic protein synthesis might contribute to the pathogenesis of ASD and other intellectual disabilities (IDs) with ASD-like clinical features. Specifically, the mTOR and MAPK signalling pathways are two key regulators of synaptogenesis and local protein synthesis in the brain. Interestingly, compelling evidence implicated those two pathways and, ultimately, protein synthesis, in syndromic autism and little is known about non-syndromic autism. Therefore, the identification of a molecular signature of ASD and disease’s severity will support the clinicians for an early diagnosis.
Objectives:
This study aims to characterize the mTOR and MAPK pathways in peripheral blood of children with idiopathic autism in order to identify a molecular signature in subjects affected by mild and severe idiopathic autism.
Methods:
A total of 55 subjects were enrolled: 33 ASD patients (aged between 3-11 years; 27 males, 6 females) and 22 healthy children as controls (aged between 3-17 years; 10 males, 12 females). A standardized clinical assessment of developmental level (psychoeducational profile third edition- PEP-3) and autistic symptoms (Autism Diagnostic Observation Schedule-ADOS) was performed for each patient. Components of the mTOR and the MAPK signalling pathways were analysed from peripheral blood at the protein level. Patients were next grouped according to their clinical phenotypes and the molecular profiling was analyzed according to the severity degree of ASD.
Results:
Increased activity of the mTOR and the MAPK pathways, emerged in patients with idiopathic ASD. Intriguingly, we observed differential expression of the MAPK and mTOR pathways according to the clinical profile of patients. Specifically, p-eIF4E, rpS6 and p-MNK1 proteins exhibited significantly increased levels in the severe group compared to controls (p-eIF4E: p = 0.0003; rpS6: p = 0.03; p-MNK1: p = 0.01;). Furthermore, we observed an increase of TSC1 levels in the mild ASD subgroup but not in the severe subgroup (p = 0.048).
Conclusions:
Our data show that an increase in both the MAPK and mTOR pathways possibly leads to aberrant protein synthesis in subjects with ASD, indicating that alteration of mTOR and the MAPK pathways may contribute to intellectual disabilities and to both syndromic and non-syndromic ASD. Moreover, our findings suggest that mild and severe autism may be discriminated according to different protein expression profiles. Although further studies in different cohorts are required, we suggest that components of protein synthesis signalling pathways might be considered as a molecular signature of clinical severity in Autism Spectrum Disorder.