Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment

Abstract

Mutations affecting mTOR or RAS signaling underlie defined syndromes (the so-called mTORopathies and RASopathies) with high risk for Autism Spectrum Disorder (ASD). These syndromes show a broad variety of somatic phenotypes including cancers, skin abnormalities, heart disease and facial dysmorphisms. Less well studied are the neuropsychiatric symptoms such as ASD. Here, we assess the relevance of these signalopathies in ASD reviewing genetic, human cell model, rodent studies and clinical trials. We conclude that signalopathies have an increased liability for ASD and that, in particular, ASD individuals with dysmorphic features and intellectual disability (ID) have a higher chance for disruptive mutations in RAS- and mTOR-related genes. Studies on rodent and human cell models confirm aberrant neuronal development as the underlying pathology. Human studies further suggest that multiple hits are necessary to induce the respective phenotypes. Recent clinical trials do only report improvements for comorbid conditions such as epilepsy or cancer but not for behavioral aspects. Animal models show that treatment during early development can rescue behavioral phenotypes. Taken together, we suggest investigating the differential roles of mTOR and RAS signaling in both human and rodent models, and to test drug treatment both during and after neuronal development in the available model systems.

From Genes to Therapy in Autism Spectrum Disorder

“…Indeed, the earlier the expression, the greater the clinical intersection between ASD and developmental delay [ 19 ]. Similar findings were highlighted by Vasic et al, providing a rationale for the importance of timing interventions early in development [ 20 ]. These and other studies suggest that many of the synaptic genes found to be associated with ASD are expressed prenatally and throughout early development, spatially and temporally coinciding with synaptic organization in brain regions relevant for ASD.…”

“…One of these convergent pathways, indicated by the involvement of several genes in which pathogenic variants can increase the probability of ASD, is synaptic function: this pathway has been discussed in several contributions present in this Special Issue. For example, Vasic et al [ 20 ]. discuss the connections between observations in humans and those derived from murine studies of genes involved in so-called “signalopathies”, including PTEN , TSC1 , TSC2 and NF1 , and how their point of convergence is abnormal synaptic function [ 20 ].…”

“…For example, Vasic et al [ 20 ]. discuss the connections between observations in humans and those derived from murine studies of genes involved in so-called “signalopathies”, including PTEN , TSC1 , TSC2 and NF1 , and how their point of convergence is abnormal synaptic function [ 20 ]. A potential role of disrupted synaptic function is also inferred from the association with ASD of genes such as SHANK3 —the gene central to Phelan–McDermid Syndrome-, NRXN1 and CNTNAP2 .…”

“…These observations underscore their potential as early biomarker of ASD [ 47 ] and as clinical endpoint measure in trials, such as proposed by the BRAINMODEL project [ 11 ]. The rationale for such novel approaches is further strengthened by the observation of sensory abnormalities in mouse models of various genetic variants associated with ASD [ 20 , 30 , 48 ]. Disruptions of synaptic function, such as those leading to disturbances in the excitation-inhibition homeostasis [ 49 ] or to loss of synaptic scaling [ 50 ], may well underlie abnormal sensory processing, providing further evidence for the link between certain pathogenic genetic variants and this component of the ASD phenotype.…”

Developing Gene-Based Personalised Interventions in Autism Spectrum Disorders

“…A promising approach in delineating the functional consequences of genetic risk factors aims to study molecular or neural mechanisms, which show overlapping characteristics between species. For example, the role of mutations in the mTOR or RAS signalling pathways show similar neuropathological characteristics in human and rodent models [ 16 ]. Gene expression pattern, neural synaptic function, or the imbalance of inhibitory and excitatory neural functions are other well-studied aspects which can be compared between rodent and human models [ 13 , 17 , 18 ].…”