Dysregulated Translation in Neurodevelopmental Disorders: An Overview of Autism‐Risk Genes Involved in Translation

Abstract

Regulated local translation—whereby specific mRNAs are transported and localized in subcellular domains where they are translated in response to regional signals—allows for remote control of gene expression to concentrate proteins in subcellular compartments. Neurons are highly polarized cells with unique features favoring local control for axonal pathfinding and synaptic plasticity, which are key processes involved in constructing functional circuits in the developing brain. Neurodevelopmental disorders are caused by genetic or environmental factors that disturb the nervous system’s development during prenatal and early childhood periods. The growing list of genetic mutations that affect mRNA translation raises the question of whether aberrant translatomes in individuals with neurodevelopmental disorders share common molecular features underlying their stereotypical phenotypes and, vice versa, cause a certain degree of phenotypic heterogeneity. Here, we briefly give an overview of the role of local translation during neuronal development. We take the autism‐risk gene list and discuss the molecules that (perhaps) are involved in mRNA transport and translation. Both exaggerated and suppressed translation caused by mutations in those genes have been identified or suggested. Finally, we discuss some proof‐of‐principle regimens for use in autism mouse models to correct dysregulated translation.

Behavioural and brain ultrastructural changes following the systemic administration of propionic acid in adolescent male rats. Further development of a rodent model of autism

“…Autism spectrum disorders (ASDs) are highly heritable, complex and pervasive conditions, characterized by communication deficits, restricted interests, emotional problems and cognitive impairments. Many genes traditionally thought to be involved in autism encode cell adhesion molecules and proteins involved in neurogenesis, synaptogenesis, synaptic functions and other cellular processes (Chen, Chang, & Huang, ; Guang et al, ; Zhao et al, ). In addition to the genetic component, a number of environmental factors participate in autism pathogenesis, affecting synapse activities, neuroimmune regulation, gastrointestinal function, metabolism and gene expression (Choi et al, ; Huang & Jin, ; MacFabe, ; Rizzetto, Fava, Tuohy, & Selmi, ).…”

The Role of Dynamic miRISC During Neuronal Development

“…Recent SFARI study has identified missense mutations in miRISC proteins AGO1, TNRC6B, and CNOT3 among patients diagnosed with Autism Spectrum Disorders (Chen et al, 2019) Patients with microdeletions of chromosomal region 1p34.3 encompassing the AGO1 and AGO3 genes also show several neurodevelopmental defects (Tokita et al, 2015). Similarly, studies have also identified a crucial role of miRISC in neurodegenerative disorders.…”

“…Finally, it is important to highlight the role of the dynamic composition of miRISC in normal neuronal development as well as its potential implication in disorders of neuronal development. Indeed, defective translational regulation is a common feature of multiple neurodevelopmental and neuropsychiatric disorders (Kapur et al, 2017;Chen et al, 2019;Neelagandan et al, 2019;Zhou et al, 2019). The role of miRNA mediated regulation of gene expression has been widely studied in these disease conditions.…”

Synaptic Formation, Neural Circuits and Neurodevelopmental Disorders Controlled by Signaling, Translation, and Epigenetic Regulation

“…The PI3K‐mTOR and RAS‐ERK signal pathways are well known to control protein synthesis by phosphorylating several translation components (Chen et al ., ), and they play critical roles in neurodevelopmental disorders. Apart from these two pathways, many kinases influence neural development via other mechanisms.…”

“…Whole‐exome sequencing of autism patients has identified additional RNA‐binding proteins. In the review article contributed by Chen and colleagues (Chen et al ., ), those RNA‐binding proteins collected in the SFARI database (https://gene.sfari.org/database/human-gene/) are categorized into four groups, namely: (1) general translation components and their regulators; (2) proteins involved in translational control via miRNA‐induced silencing complexes; (3) target‐specific proteins controlled by RNA‐binding proteins and their partners; and (4) signaling molecules that control translation. Chen and colleagues provide a comprehensive summary and discussion of this topic in this Special Issue (Chen et al ., ).…”