Genome-Scale Networks Link Neurodegenerative Disease Genes to α-Synuclein through Specific Molecular Pathways.
Genome-Scale Networks Link Neurodegenerative Disease Genes to α-Synuclein through Specific Molecular Pathways.
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DOI：
10.1016/j.cels.2016.12.011
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发表时间：
2017-02-22
期刊：
影响因子：
9.3
通讯作者：
Lindquist S
中科院分区：
文献类型：
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作者：
Khurana V;Peng J;Chung CY;Auluck PK;Fanning S;Tardiff DF;Bartels T;Koeva M;Eichhorn SW;Benyamini H;Lou Y;Nutter-Upham A;Baru V;Freyzon Y;Tuncbag N;Costanzo M;San Luis BJ;Schöndorf DC;Barrasa MI;Ehsani S;Sanjana N;Zhong Q;Gasser T;Bartel DP;Vidal M;Deleidi M;Boone C;Fraenkel E;Berger B;Lindquist S
许多基因和分子途径与神经退行性蛋白质病有关，但人们对它们之间的相互关系知之甚少。我们系统地绘制了α-突触核蛋白（α-syn）毒性的分子途径，α-突触核蛋白是帕金森病的核心蛋白质。酵母全基因组筛选鉴定出 332 个影响 α-syn 毒性的基因。为了“人性化”这个分子网络，我们开发了一种计算方法 TransposeNet。这将斯坦纳奖收集方法与通过序列、结构和相互作用拓扑的同源分配相结合。 TransposeNet 通过扰乱蛋白质运输/ER 质量控制和 mRNA 代谢/翻译，将 α-syn 与多个帕金森病基因和可药物靶标连接起来。钙信号传导中枢将这些过程与扰动的线粒体质量控制/功能、金属离子转运、转录调节和信号转导联系起来。网络中空间相对的帕金森病基因相互作用谱（ATP13A2/PARK9、VPS35/PARK17）高度不同，并且在患者 iPS 细胞衍生的神经元中证实了特定基因（LRRK2/PARK8、ATXN2 和 EIF4G1/PARK18）的网络关系。这个跨物种平台通过特定机制将不同的神经退行性基因与蛋白质病联系起来，并可能促进患者分层以进行靶向治疗。
Numerous genes and molecular pathways are implicated in neurodegenerative proteinopathies, but their inter-relationships are poorly understood. We systematically mapped molecular pathways underlying the toxicity of alpha-synuclein (α-syn), a protein central to Parkinson’s disease. Genome-wide screens in yeast identified 332 genes that impact α-syn toxicity. To “humanize” this molecular network, we developed a computational method, TransposeNet. This integrates a Steiner prize-collecting approach with homology assignment through sequence, structure and interaction topology. TransposeNet linked α-syn to multiple parkinsonism genes and druggable targets through perturbed protein trafficking/ER quality control and mRNA metabolism/translation. A calcium signaling hub linked these processes to perturbed mitochondrial quality control/function, metal ion transport, transcriptional regulation and signal transduction. Parkinsonism gene interaction profiles spatially opposed in the network (ATP13A2/PARK9, VPS35/PARK17) were highly distinct, and network relationships for specific genes (LRRK2/PARK8, ATXN2 and EIF4G1/PARK18) were confirmed in patient iPS cell-derived neurons. This cross-species platform connected diverse neurodegenerative genes to proteinopathy through specific mechanisms, and may facilitate patient stratification for targeted therapy.