Increased expression of SLC25A1/CIC in the mouse results in an autistic-like phenotype with altered white matter microstructure and neuron morphology

Ne-lysine acetylation within the lumen of the endoplasmic reticulum (ER) is a recently characterized protein quality control system that positively selects properly folded glycoproteins in the early secretory pathway. Overexpression of the ER acetyl-CoA transporter AT-1 in mouse forebrain neurons results in increased dendritic branching, spine formation, and an autistic-like phenotype that is attributed to altered glycoprotein flux through the secretory pathway. AT-1 overexpressing neurons maintain the cytosolic pool of acetyl-CoA by upregulation of SLC25A1, the mitochondrial citrate/malate antiporter, and ATP citrate lyase (ACLY), which converts cytosolic citrate into acetyl-CoA. All three genes have been associated with autism spectrum disorder (ASD), suggesting that aberrant cytosolic to ER flux of acetyl-CoA can be a mechanistic driver for the development of ASD. We therefore generated a SLC25A1 neuron transgenic (nTg) mouse, which displayed autistic-like behaviors with a jumping stereotypy. The mice exhibited increased steady-state levels of citrate and acetyl-CoA, disrupted white matter integrity with activated microglia, and altered synaptic plasticity and morphology. Finally, acetylomic and proteomic analysis revealed differential adaptations in the hippocampus and cortex. Overall, our study reinforces the connection between aberrant cytosol-to-ER flux of acetyl-CoA flux and the development of an autistic-like phenotype.

内质网（endoplasmic reticulum, ER）腔室内的Nε-赖氨酸乙酰化是新近被鉴定的蛋白质质量控制系统，可在分泌途径早期正向筛选正确折叠的糖蛋白。在小鼠前脑神经元中过表达内质网乙酰辅酶A转运蛋白AT-1（acetyl-CoA transporter AT-1），会导致树突分支增多、突触棘形成增加，并出现自闭症样表型，该表型被认为与分泌途径中糖蛋白通量异常相关。过表达AT-1的神经元通过上调SLC25A1——一种线粒体柠檬酸/苹果酸反向转运体——以及将胞质柠檬酸转化为乙酰辅酶A的ATP柠檬酸裂解酶（ATP citrate lyase, ACLY），来维持胞质乙酰辅酶A池。上述三个基因均与自闭症谱系障碍（autism spectrum disorder, ASD）相关，这提示异常的胞质向内质网的乙酰辅酶A通量可能是自闭症谱系障碍发生的机制性驱动因素。为此，我们构建了SLC25A1神经元特异性转基因（neuron transgenic, nTg）小鼠，该模型表现出伴有跳跃刻板行为的自闭症样行为。这些小鼠的柠檬酸和乙酰辅酶A稳态水平升高，白质完整性受损且小胶质细胞活化，同时突触可塑性与突触形态发生改变。最后，乙酰化组学与蛋白质组学分析显示，小鼠海马体与大脑皮层存在差异性适应。综上，本研究进一步证实了异常的胞质-内质网乙酰辅酶A通量与自闭症样表型发生之间的关联。