Synthetic lethal screening in the mammalian central nervous system identifies Gpx6 as a modulator of Huntington's disease.
Synthetic lethal screening in the mammalian central nervous system identifies Gpx6 as a modulator of Huntington's disease.
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哺乳动物中枢神经系统的综合致死筛选确定 Gpx6 是亨廷顿病的调节剂。
DOI：
10.1073/pnas.1417231112
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发表时间：
2015
影响因子：
11.1
通讯作者：
Heiman,Myriam
中科院分区：
文献类型：
--
作者：
Shema,Reut;Kulicke,Ruth;Cowley,GlennS;Stein,Rachael;Root,DavidE;Heiman,Myriam
亨廷顿病是最常见的遗传性神经退行性疾病，其特征在于深层皮质和纹状体神经元的急剧丧失，以及中年发病率。人类遗传学研究导致了致病基因亨廷顿蛋白的鉴定。最近的基因组学进展也导致了数百个潜在的相互作用的合作伙伴亨廷顿蛋白和许多假说的分子机制，突变亨廷顿蛋白导致细胞功能障碍和死亡的鉴定。然而，许多可能的相互作用的合作伙伴和受突变亨廷顿蛋白影响的细胞途径复杂的努力，以了解这种疾病的病因，迄今为止，没有治愈性治疗存在。为了解决从大量相关研究中识别疾病表型贡献基因的一般问题，在这里，我们开发了一种用于哺乳动物中枢神经系统的合成致死筛选方法，称为SLIC，用于中枢神经系统的合成致死。将SLIC应用于亨廷顿病的研究，我们确定了年龄调节型谷胱甘肽过氧化物酶6（Gpx 6）基因作为突变亨廷顿毒性的调节剂，并表明Gpx 6的过表达可以显着减轻与亨廷顿病小鼠模型相关的行为和分子表型。原则上，SLIC可以用于研究任何存在小鼠模型的神经退行性疾病，有望以无偏的方式揭示神经退行性疾病的调节剂，类似于在更简单的模型生物体中进行筛选。
Huntington’s disease, the most common inherited neurodegenerative disease, is characterized by a dramatic loss of deep-layer cortical and striatal neurons, as well as morbidity in midlife. Human genetic studies led to the identification of the causative gene,huntingtin. Recent genomic advances have also led to the identification of hundreds of potential interacting partners for huntingtin protein and many hypotheses as to the molecular mechanisms whereby mutant huntingtin leads to cellular dysfunction and death. However, the multitude of possible interacting partners and cellular pathways affected by mutant huntingtin has complicated efforts to understand the etiology of this disease, and to date no curative therapeutic exists. To address the general problem of identifying the disease-phenotype contributing genes from a large number of correlative studies, here we develop a synthetic lethal screening methodology for the mammalian central nervous system, called SLIC, for synthetic lethal in the central nervous system. Applying SLIC to the study of Huntington’s disease, we identify the age-regulated glutathione peroxidase 6 (Gpx6) gene as a modulator of mutant huntingtin toxicity and show that overexpression of Gpx6 can dramatically alleviate both behavioral and molecular phenotypes associated with a mouse model of Huntington’s disease. SLIC can, in principle, be used in the study of any neurodegenerative disease for which a mouse model exists, promising to reveal modulators of neurodegenerative disease in an unbiased fashion, akin to screens in simpler model organisms.