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Abstract：
Neurodevelopmental disorders offer insight into synaptic mechanisms. To unbiasedly uncover these mechanisms, we studied the 22q11.2 syndrome, a recurrent copy number variant, which is the highest schizophrenia genetic risk factor. We quantified the proteomes of 22q11.2 mutant human fibroblasts from both sexes and mouse brains carrying a 22q11.2-like defect, Df(16)A+/- Molecular ontologies defined mitochondrial compartments and pathways as some of top ranked categories. In particular, we identified perturbations in the SLC25A1-SLC25A4 mitochondrial transporter interactome as associated with the 22q11.2 genetic defect. Expression of SLC25A1-SLC25A4 interactome components was affected in neuronal cells from schizophrenia patients. Furthermore, hemideficiency of the Drosophila SLC25A1 or SLC25A4 orthologues, dSLC25A1-sea and dSLC25A4-sesB, affected synapse morphology, neurotransmission, plasticity, and sleep patterns. Our findings indicate that synapses are sensitive to partial loss of function of mitochondrial solute transporters. We propose that mitoproteomes regulate synapse development and function in normal and pathological conditions in a cell-specific manner.SIGNIFICANCE STATEMENT We address the central question of how to comprehensively define molecular mechanisms of the most prevalent and penetrant microdeletion associated with neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. This complex mutation reduces gene dosage of ∼63 genes in humans. We describe a disruption of the mitoproteome in 22q11.2 patients and brains of a 22q11.2 mouse model. In particular, we identify a network of inner mitochondrial membrane transporters as a hub required for synapse function. Our findings suggest that mitochondrial composition and function modulate the risk of neurodevelopmental disorders, such as schizophrenia.
摘要：
神经发育障碍提供了对突触机制的洞察。为了无偏见地发现这些机制，我们研究了22q11.2综合征，重复拷贝数变异，这是精神分裂症遗传风险最高的因素。我们定量了22q11.2突变的人类成纤维细胞的蛋白质组，来自两性和携带22q11.2样缺陷的小鼠大脑，Df(16)A+/-分子本体论将线粒体区室和途径定义为一些顶级类别。特别是,我们发现SLC25A1-SLC25A4线粒体转运蛋白相互作用组的扰动与22q11.2基因缺陷相关.SLC25A1-SLC25A4相互作用组成分的表达在精神分裂症患者的神经元细胞中受到影响。此外，果蝇SLC25A1或SLC25A4直系同源物的半缺乏症，dSLC25A1-sea和dSLC25A4-sesB，受影响的突触形态，神经传递,可塑性,和睡眠模式。我们的发现表明，突触对线粒体溶质转运蛋白功能的部分丧失敏感。我们建议有丝分裂蛋白质组以细胞特异性方式调节正常和病理条件下的突触发育和功能。我们解决的核心问题是如何全面定义与神经发育障碍相关的最普遍和渗透微缺失的分子机制，22q11.2微缺失综合征。这种复杂的突变减少了人类中~63个基因的基因剂量。我们描述了22q11.2患者和22q11.2小鼠模型的大脑中的有丝分裂蛋白质组的破坏。特别是,我们确定了线粒体内膜转运蛋白网络作为突触功能所需的枢纽。我们的研究结果表明，线粒体组成和功能调节神经发育障碍的风险，比如精神分裂症。
