Cilia interactome with predicted protein-protein interactions reveals connections to Alzheimer's disease, aging and other neuropsychiatric processes.
Cilia interactome with predicted protein-protein interactions reveals connections to Alzheimer's disease, aging and other neuropsychiatric processes.
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DOI：
10.1038/s41598-020-72024-4
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发表时间：
2020-09-24
影响因子：
4.6
通讯作者：
Ganapathiraju MK
中科院分区：
文献类型：
--
作者：
Karunakaran KB;Chaparala S;Lo CW;Ganapathiraju MK
纤毛是存在于许多真核细胞类型的表面上的基于微管的动态细胞器，并且可以是运动的或非运动的初级纤毛。纤毛缺陷是越来越多的人类疾病的基础，统称为纤毛病，具有重叠的表型，如发育迟缓和认知和记忆缺陷。与此相一致，纤毛在脑发育中起着重要作用，特别是在神经发生和神经元迁移中。这些发现表明，更深入的系统水平的了解如何睫状蛋白一起发挥作用，可能会提供新的机制的见解神经系统缺陷的分子病因。为此，我们进行了蛋白质-蛋白质相互作用（PPI）的网络分析已知的鞭毛内运输，BBSome，过渡区，纤毛膜和运动纤毛蛋白。纤毛蛋白的已知PPI是从在线数据库中组装的。使用我们开发的称为高精度PPI预测（HiPPIP）模型的计算方法预测每种纤毛蛋白的新型PPI。由此产生的纤毛“相互作用组”由165种纤毛蛋白、1,011种已知PPI和765种新型PPI组成。纤毛相互作用组揭示了纤毛蛋白之间的相互联系，以及它们与神经精神过程相关的几种途径和药物靶点的关系。纤毛相互作用组中大约184个基因被548种目前批准的药物靶向，其中103种用于治疗各种神经系统起源的疾病。两者合计，纤毛相互作用组提供了新的见解纤毛蛋白功能障碍和神经精神疾病之间的关系，例如阿尔茨海默病，衰老和纤毛基因的相互联系。这些结果提供了一个框架，用于治疗纤毛疾病和神经精神疾病的新的治疗药物的合理设计。
Cilia are dynamic microtubule-based organelles present on the surface of many eukaryotic cell types and can be motile or non-motile primary cilia. Cilia defects underlie a growing list of human disorders, collectively called ciliopathies, with overlapping phenotypes such as developmental delays and cognitive and memory deficits. Consistent with this, cilia play an important role in brain development, particularly in neurogenesis and neuronal migration. These findings suggest that a deeper systems-level understanding of how ciliary proteins function together may provide new mechanistic insights into the molecular etiologies of nervous system defects. Towards this end, we performed a protein–protein interaction (PPI) network analysis of known intraflagellar transport, BBSome, transition zone, ciliary membrane and motile cilia proteins. Known PPIs of ciliary proteins were assembled from online databases. Novel PPIs were predicted for each ciliary protein using a computational method we developed, called High-precision PPI Prediction (HiPPIP) model. The resulting cilia “interactome” consists of 165 ciliary proteins, 1,011 known PPIs, and 765 novel PPIs. The cilia interactome revealed interconnections between ciliary proteins, and their relation to several pathways related to neuropsychiatric processes, and to drug targets. Approximately 184 genes in the cilia interactome are targeted by 548 currently approved drugs, of which 103 are used to treat various diseases of nervous system origin. Taken together, the cilia interactome presented here provides novel insights into the relationship between ciliary protein dysfunction and neuropsychiatric disorders, for e.g. interconnections of Alzheimer’s disease, aging and cilia genes. These results provide the framework for the rational design of new therapeutic agents for treatment of ciliopathies and neuropsychiatric disorders.
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影响因子：
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