Lu Ming-Hsuan, Hsueh Yi-Ping
Department of Medical Education, National Taiwan University Hospital, Taipei, Taiwan, ROC.
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, ROC.
FEBS J. 2022 Apr;289(8):2282-2300. doi: 10.1111/febs.15733. Epub 2021 Feb 22.
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 whether 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.
自闭症谱系障碍（ASD）越来越被认为是一种大脑连接改变的病症。由于突触是神经元连接的基本亚细胞结构，突触病理生理学已成为自闭症研究的核心主题之一。关于在ASD中树突棘（即兴奋性突触）的密度是增加还是减少，以及对树突棘形成和功能至关重要的蛋白质合成是上调还是下调，各报告意见不一。在这里，我们综述了支持树突棘密度降低的ASD模型亚组（以下简称ASD-DSD）的最新证据，包括Nf1和Vcp突变小鼠。我们讨论了支链氨基酸（BCAA）不足与ASD-DSD中未满足的蛋白质合成需求之间的相关性。与ASD-DSD相反，具有雷帕霉素哺乳动物靶标（mTOR）过度活跃的ASD模型可能代表疾病谱的另一端，其特征通常是蛋白质合成和树突棘密度增加（称为ASD-ISD）。最后，我们提出个性化的膳食亮氨酸作为一种策略，旨在平衡蛋白质合成需求，从而改善易感患者尤其是ASD-DSD患者的树突棘病理生理学和自闭症相关表型。
