Autism spectrum disorder (ASD) is defined by common behavioral characteristics, raising the possibility of shared pathogenic mechanisms. Yet, vast clinical and etiological heterogeneity suggests personalized phenotypes. Surprisingly, our iPSC studies find that six individuals from two distinct ASD-subtypes, idiopathic and 16p11.2 deletion, have common reductions in neural precursor cell (NPC) neurite outgrowth and migration even though whole genome sequencing demonstrates no genetic overlap between the datasets. To identify signaling differences that may contribute to these developmental defects, an unbiased phospho-(p)-proteome screen was performed. Surprisingly despite the genetic heterogeneity, hundreds of shared p-peptides were identified between autism subtypes including the mTOR pathway. mTOR signaling alterations were confirmed in all NPCs across both ASD-subtypes, and mTOR modulation rescued ASD phenotypes and reproduced autism NPC associated phenotypes in control NPCs. Thus, our studies demonstrate that genetically distinct ASD subtypes have common defects in neurite outgrowth and migration which are driven by the shared pathogenic mechanism of mTOR signaling dysregulation.

中文翻译：

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mTOR 信号传导失调介导特发性和 16p11.2 缺失自闭症神经前体细胞中的常见神经突和迁移缺陷

自闭症谱系障碍（ASD）是由共同的行为特征定义的，这增加了共同致病机制的可能性。然而，巨大的临床和病因学异质性表明个性化表型。令人惊讶的是，我们的 iPSC 研究发现，来自两种不同 ASD 亚型（特发性和 16p11.2 缺失）的 6 个个体的神经前体细胞 (NPC) 神经突生长和迁移普遍减少，尽管全基因组测序表明数据集之间没有遗传重叠。为了识别可能导致这些发育缺陷的信号差异，进行了无偏磷酸-(p)-蛋白质组筛选。令人惊讶的是，尽管存在遗传异质性，但在自闭症亚型之间发现了数百种共享的 p 肽，包括 mTOR 通路。 mTOR 信号改变在所有 ASD 亚型的 NPC 中均得到证实，mTOR 调节可挽救 ASD 表型，并在对照 NPC 中重现自闭症 NPC 相关表型。因此，我们的研究表明，遗传上不同的 ASD 亚型在神经突生长和迁移方面具有共同的缺陷，这是由 mTOR 信号传导失调的共同致病机制驱动的。