Dysregulation of translational control signaling in autism spectrum disorders

Abstract

Deviations from the optimal level of mRNA translation are linked to disorders with high rates of autism. Loss of function mutations in genes encoding translational repressors such as PTEN, TSC1, TSC2, and FMRP are associated with autism spectrum disorders (ASDs) in humans and their deletion in animals recapitulates many ASD-like phenotypes. Importantly, the activity of key translational control signaling pathways such as PI3K-mTORC1 and ERK is frequently dysregulated in autistic patients and animal models and their normalization rescues many abnormal phenotypes, suggesting a causal relationship. Mutations in several genes encoding proteins not directly involved in translational control have also been shown to mediate ASD phenotypes via altered signaling upstream of translation. This raises the possibility that the dysregulation of translational control signaling is a converging mechanism not only in familiar but also in sporadic forms of autism. Here, we overview the current knowledge on translational signaling in ASD and highlight how correcting the activity of key pathways upstream of translation reverses distinct ASD-like phenotypes.