Genome-Wide Genetic Screening in the Mammalian CNS

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.