Shema Reut, Kulicke Ruth, Cowley Glenn S, Stein Rachael, Root David E, Heiman Myriam
The Broad Institute of MIT and Harvard University, Cambridge, MA 02142; The Picower Institute for Learning and Memory, Cambridge, MA 02139; and.
The Broad Institute of MIT and Harvard University, Cambridge, MA 02142;
Proc Natl Acad Sci U S A. 2015 Jan 6;112(1):268-72. doi: 10.1073/pnas.1417231112. Epub 2014 Dec 22.
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.
亨廷顿舞蹈症是最常见的遗传性神经退行性疾病，其特征是深层皮质和纹状体神经元大量丧失，以及中年发病。人类遗传学研究确定了致病基因亨廷顿蛋白。最近的基因组学进展还确定了数百种亨廷顿蛋白的潜在相互作用伙伴，并提出了许多关于突变型亨廷顿蛋白导致细胞功能障碍和死亡的分子机制的假说。然而，突变型亨廷顿蛋白影响的众多可能的相互作用伙伴和细胞途径使理解这种疾病的病因变得复杂，并且迄今为止尚无治愈性疗法。为了解决从大量相关性研究中识别疾病表型贡献基因的普遍问题，我们在此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，称为中枢神经系统合成致死筛选法（SLIC）。将SLIC应用于亨廷顿舞蹈症的研究，我们确定年龄调节型谷胱甘肽过氧化物酶6（Gpx6）基因为突变型亨廷顿蛋白毒性的调节因子，并表明Gpx6的过表达可以显著减轻与亨廷顿舞蹈症小鼠模型相关联的行为和分子表型。原则上，SLIC可用于任何存在小鼠模型的神经退行性疾病的研究，有望以无偏见的方式揭示神经退行性疾病的调节因子，类似于在更简单的模式生物中的筛选。
