Wertz Mary H., Heiman Myriam
Picower Institute for Learning and Memory, Cambridge, MA, 02139, USA
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Genes linked to major neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, were first identified over 15 years ago, but neither a full molecular explanation for the cell loss seen in human patients nor a curative therapy has yet been achieved for any of these diseases. In most model organisms, when new hypotheses are needed to explain a cellular process, genetic screens are the tool of choice. For example, ‘synthetic lethal’ screens can lead to the identification of genes that enhance the toxicity of a particular mutation, revealing pathways critical for surviving the mutation’s effects. To date, however, genome-wide unbiased screens are not feasible in mammalian central nervous system neurons except in vitro, which fails to capture the relevant disease pathologies, and no genome-wide screens have yet been conducted in the mammalian central nervous system. We outline in this short monograph the steps needed to implement a methodology that allows for genome-wide genetic screening in the central nervous system of mice to study both normal and degenerative disease gene function.
与包括阿尔茨海默病、帕金森病和亨廷顿病在内的主要神经退行性疾病相关的基因，早在15年多以前就已首次被发现，但对于这些疾病中的任何一种，既没有对人类患者中所见细胞损失的完整分子解释，也尚未找到治愈性疗法。在大多数模式生物中，当需要新的假说来解释细胞过程时，基因筛选是首选工具。例如，“合成致死”筛选可导致识别出增强特定突变毒性的基因，从而揭示对抵御突变影响至关重要的途径。然而，迄今为止，除了在体外进行外，全基因组无偏筛选在哺乳动物中枢神经系统神经元中并不可行，而体外筛选无法捕捉相关疾病病理情况，并且尚未在哺乳动物中枢神经系统中进行过全基因组筛选。在这本简短的专著中，我们概述了实施一种方法所需的步骤，该方法能够在小鼠中枢神经系统中进行全基因组遗传筛选，以研究正常和退行性疾病基因功能。
