Local Protein Translation and RNA Processing of Synaptic Proteins in Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) is a heritable neurodevelopmental condition associated with impairments in social interaction, communication and repetitive behaviors. While the underlying disease mechanisms remain to be fully elucidated, dysfunction of neuronal plasticity and local translation control have emerged as key points of interest. Translation of mRNAs for critical synaptic proteins are negatively regulated by Fragile X mental retardation protein (FMRP), which is lost in the most common single-gene disorder associated with ASD. Numerous studies have shown that mRNA transport, RNA metabolism, and translation of synaptic proteins are important for neuronal health, synaptic plasticity, and learning and memory. Accordingly, dysfunction of these mechanisms may contribute to the abnormal brain function observed in individuals with autism spectrum disorder (ASD). In this review, we summarize recent studies about local translation and mRNA processing of synaptic proteins and discuss how perturbations of these processes may be related to the pathophysiology of ASD.

Synaptic Alterations in a Transgenic Model of Tuberous Sclerosis Complex: Relevance to Autism Spectrum Disorders

“…Interestingly, the impairment of the endoplasmic reticulum, an increased fraction of free polyribosomes, and the impairment of the Golgi apparatus may indicate that local protein synthesis, modification, and transport in Tsc2 +/−- animals may be the crucial pathological event triggering further perturbations. Abnormal translation at the synapse was suggested to contribute to the pathological mechanisms of ASD [ 43 ].…”

SHANK2 Mutations Result in Dysregulation of the ERK1/2 Pathway in Human Induced Pluripotent Stem Cells-Derived Neurons and Shank2(−/−) Mice

“…Different ASD models show changes in E-I balance (Dickinson et al, 2016), and studies on human mid-fetal circuits showed that the deformation of connectivity and neuronal networks emerge already early in neurodevelopment (Parikshak et al, 2013;Willsey et al, 2013). Other hypotheses concentrate on the critical role of dysregulated mRNA translation (Monteiro and Feng, 2017;Joo and Benavides, 2021) or signaling pathways (Zoghbi and Bear, 2012;Kleijer et al, 2014). In this respect, the extracellular signal-regulated kinase (ERK) pathway seems to play a central role in the pathogenesis of ASD (Faridar et al, 2014;Vithayathil et al, 2018).…”

Interaction studies of risk proteins in human induced neurons reveal convergent biology and novel mechanisms underlying autism spectrum disorders

“…Insulin-like growth factor 2 mRNA-binding proteins 1-3 (IGF2BP1-3) were recently characterized as part of a N6-methyladenosine (m6A)-reader complex broadly involved in post-transcriptional regulation by impacting mRNA stability and translation rates ( 48 ). Numerous studies have shown that mRNA transport, turnover, and translation of synaptic proteins are key to maintaining neuronal health, synaptic plasticity, learning, and memory ( 74 ), and m6A deposition has emerged as a critical regulatory mechanism for these functions in neurons and neural progenitors ( 75–78 ). Growing evidence has also linked FMRP (Fragile X mental retardation protein, named after the most common single-gene disorder associated with ASDs) and its role in synaptic protein regulation to its binding of m6A-modified transcripts ( 79 ).…”

“…Numerous studies have shown that mRNA transport, turnover, and translation of synaptic proteins are key to maintaining neuronal health, synaptic plasticity, learning, and memory (74), and m6A deposition has emerged as a critical regulatory mechanism for these functions in neurons and neural progenitors (75)(76)(77)(78). Growing evidence has also linked FMRP (Fragile X mental retardation protein, named after the most common single-gene disorder associated with ASDs) and its role in synaptic protein regulation to its binding of m6A-modified transcripts (79).…”