Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.

中文翻译：

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介导神经退行性痴呆的进化保守基因网络的鉴定。

确定遗传风险导致痴呆症的机制是新疗法开发的当务之急。在这里，我们应用多阶段系统生物学方法来阐明额颞叶痴呆的疾病机制。我们确定了两个基因共表达模块，它们保存在携带 MAPT、GRN 突变和不同遗传背景的其他痴呆突变的小鼠中。我们通过整合来自人脑的蛋白质组学和转录组学数据来弥合物种鸿沟，以识别进化上保守的、与疾病相关的网络。我们发现 miR-203 的过表达是假定的调节性 microRNA (miRNA) 模块的中心，它概括了与疾病状态相关的 mRNA 共表达模式并诱导神经元细胞死亡，从而将这种 miRNA 确立为神经变性的调节剂。使用药物介导的基因表达变化数据库，我们确定了可以使疾病相关模块正常化的小分子，并通过实验验证了这一点。我们的结果突出了综合的跨物种网络方法在药物发现中的实用性。