Autism spectrum disorder (ASD) and Alzheimer’s disease (AD) are two different neurological disorders that share common clinical features, such as language impairment, executive functions, and motor problems. A genetic convergence has been proposed as well. However, the molecular mechanisms of these pathologies are still not well understood. Protein S-nitrosylation (SNO), the nitric oxide (NO)-mediated posttranslational modification, targets key proteins implicated in synaptic and neuronal functions. Previously, we have shown that NO and SNO are involved in the InsG3680(+/+) ASD and P301S AD mouse models. Here, we performed large-scale computational biology analysis of the SNO-proteome followed by biochemical validation to decipher the shared mechanisms between the pathologies. This analysis pointed to the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway as one of the shared molecular mechanisms. Activation of mTOR in the cortex of both mouse models was confirmed by western blots that showed increased phosphorylation of RPS6, a major substrate of mTORC1. Other molecular alterations affected by SNO and shared between the two mouse models, such as synaptic-associated processes, PKA signaling, and cytoskeleton-related processes were also detected. This is the first study to decipher the SNO-related shared mechanisms between SHANK3 and MAPT mutations. Understanding the involvement of SNO in neurological disorders and its intersection between ASD and AD might help developing an effective novel therapy for both neuropathologies.

自闭症谱系障碍 (ASD) 和阿尔茨海默病 (AD) 是两种不同的神经系统疾病，具有共同的临床特征，例如语言障碍、执行功能和运动问题。还提出了遗传趋同。然而，这些病理的分子机制仍不清楚。蛋白质 S-亚硝基化 (SNO) 是一氧化氮 (NO) 介导的翻译后修饰，针对与突触和神经元功能有关的关键蛋白质。之前，我们已经证明 NO 和 SNO 参与 InsG3680(+/+) ASD 和 P301S AD 小鼠模型。在这里，我们对 SNO 蛋白质组进行了大规模计算生物学分析，然后进行生化验证，以破译病理学之间的共同机制。该分析指出哺乳动物靶点雷帕霉素复合物 1 (mTORC1) 信号通路是共享的分子机制之一。蛋白质印迹证实了两种小鼠模型皮质中 mTOR 的激活，蛋白质印迹显示 mTORC1 的主要底物 RPS6 的磷酸化增加。还检测到受 SNO 影响且两种小鼠模型共有的其他分子改变，例如突触相关过程、PKA 信号传导和细胞骨架相关过程。这是第一项破译SHANK3和MAPT突变之间 SNO 相关共享机制的研究。了解 SNO 与神经系统疾病的关系及其在 ASD 和 AD 之间的交叉可能有助于开发一种针对这两种神经病理学的有效新疗法。