Dysregulation of protein synthesis and dendritic spine morphogenesis in ASD: studies in human pluripotent stem cells

Abstract

Autism spectrum disorder (ASD) is a brain disorder that involves changes in neuronal connections. Abnormal morphology of dendritic spines on postsynaptic neurons has been observed in ASD patients and transgenic mice that model different monogenetic causes of ASD. A number of ASD-associated genetic variants are known to disrupt dendritic local protein synthesis, which is essential for spine morphogenesis, synaptic transmission, and plasticity. Most of our understanding on the molecular mechanism underlying ASD depends on studies using rodents. However, recent advance in human pluripotent stem cells and their neural differentiation provides a powerful alternative tool to understand the cellular aspects of human neurological disorders. In this review, we summarize recent progress on studying mRNA targeting and local protein synthesis in stem cell-derived neurons, and discuss how perturbation of these processes may impact synapse development and functions that are relevant to cognitive deficits in ASD.

Profiling of Sexually Dimorphic Genes in Neural Cells to Identify Eif2s3y, Whose Overexpression Causes Autism-Like Behaviors in Male Mice

“…The human homolog of Eif2s3y , EIF2S3 encodes eukaryotic translation initiation factor 2 subunit γ (eIF2γ) that plays a regulatory role in Met-tRNAi Met binding and thus is involved in early protein synthesis ( Young-Baird et al, 2019 ). Since dysregulation of protein synthesis has been found in ASD patients and animal models and proposed as a common mechanism underlying disease pathogenesis ( Levitt and Campbell, 2009 ; Lo and Lai, 2020 ; Lu and Hsueh, 2021 ), it is possible that a dysregulation of Eif2s3y may promote susceptibility to ASD through interfering with the synthesis of proteins critically involved in ASD pathogenesis; and this warrants further investigation.…”

Cell Adhesion Molecules and Protein Synthesis Regulation in Neurons

“…In this review, we draw attention to the growing body of work showing that CAMs also regulate transcription and protein translation and that the protein biosynthesis pathways play a key role in the morphological and functional changes induced by CAMs in neurons. Dysregulation of protein synthesis has been observed in different neurodevelopmental and neurodegenerative disorders, including autism spectrum disorders, fragile X syndrome, and Alzheimer’s disease (Buffington et al, 2014 ; Ghosh et al, 2020 ; Lo and Lai, 2020 ), which are also associated with abnormalities in the expression or processing of CAMs (Leshchyns’ka et al, 2015 ; Stewart, 2015 ; Leshchyns’ka and Sytnyk, 2016b ; Chmielewska et al, 2019 ). Understanding the CAM-mediated regulation of protein synthesis can provide further insight into the etiologies of these conditions and, consequently, lead to new therapies.…”

SETD1A Mediated H3K4 Methylation and Its Role in Neurodevelopmental and Neuropsychiatric Disorders

“…Indeed, Setd1a +/– mice show reduced neuronal connectivity by means of reduced spine density, particularly mushroom spine density on pyramidal neurons (Mukai et al, 2019 ; Nagahama et al, 2020 ; Figure 1D ). Dysregulated spine density is known to be associated with multiple neurological disorders, such as Down syndrome and SCZ (Geschwind and Levitt, 2007 ; Nishiyama, 2019 ; Lo and Lai, 2020 ). Furthermore, reduced axonal projections patterns of cortical neurons from Setd1a +/– mice have been suggested to result in changes in axonal connectivity (Mukai et al, 2019 ).…”