Protein synthesis as a modifiable target for autism‐related dendritic spine pathophysiologies

Abstract

Autism spectrum disorder (ASD) is increasingly recognized as a condition of altered brain connectivity. As synapses are fundamental subcellular structures for neuronal connectivity, synaptic pathophysiology has become one of central themes in autism research. Reports disagree upon whether the density of dendritic spines, namely excitatory synapses, is increased or decreased in ASD and if the protein synthesis that is critical for dendritic spine formation and function is upregulated or downregulated. Here, we review recent evidence supporting a subgroup of ASD models with decreased dendritic spine density (hereafter ASD-DSD), including Nf1 and Vcp mutant mice. We discuss the relevance of branched-chain amino acid (BCAA) insufficiency in relation to unmet protein synthesis demand in ASD-DSD. In contrast to ASD-DSD, ASD models with hyperactive mammalian target of rapamycin (mTOR) may represent the opposite end of the disease spectrum, often characterized by increases in protein synthesis and dendritic spine density (denoted ASD-ISD). Finally, we propose personalized dietary leucine as a strategy tailored to balancing protein synthesis demand, thereby ameliorating dendritic spine pathophysiologies and autism-related phenotypes in susceptible patients, especially those with ASD-DSD.

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.…”

In-vivo production of branched-chain amino acids, branched-chain keto acids, and β-hydroxy β-methylbutyric acid

“…The branched-chain amino acids (BCAA: leucine, isoleucine, valine) and its metabolites the branched-chain keto acids [BCKA: a-ketoisocaproic acid (KIC), a-ketoisovaleric acid (KIV), 3-methyl-2oxovaleric acid (KMV)] as well the KIC metabolite bhydroxy b-methylbutyric acid (HMB) have recently regained interest as food ingredients in health and disease [1][2][3][4][5][6]. They play a regulatory role in the anabolic capacity of the meal and are involved in the regulation of key signaling metabolic pathways [2].…”

Editorial: Autism Signaling Pathways

“…Finally, although it was not clearly addressed in the articles collected for this Research Topic, it is generally accepted that deviations from homeostasis (the “golden mean,” see Figure 1 ) are common in ASD. For instance, both increases and decreases in protein synthesis and signaling have been linked to ASD-associated neuronal defects (Lu and Hsueh, 2021 ). Synaptic morphology and responses must also be controlled within appropriate thresholds so that neuronal activity or function is neither excessive nor inadequate, since any such defects may lead to ASD pathological conditions.…”