Genome-wide In Vivo CNS Screening Identifies Genes that Modify CNS Neuronal Survival and mHTT Toxicity

Unbiased in vivo genome-wide genetic screening is a powerful approach to elucidate new molecular mechanisms, but such screening has not been possible to perform in the mammalian central nervous system (CNS). Here, we report the results of the first genome-wide genetic screens in the CNS using both short hairpin RNA (shRNA) and CRISPR libraries. Our screens identify many classes of CNS neuronal essential genes and demonstrate that CNS neurons are particularly sensitive not only to perturbations to synaptic processes but also autophagy, proteostasis, mRNA processing, and mitochondrial function. These results reveal a molecular logic for the common implication of these pathways across multiple neurodegenerative diseases. To further identify disease-relevant genetic modifiers, we applied our screening approach to two mouse models of Huntington’s disease (HD). Top mutant huntingtin toxicity modifier genes included several Nme genes and several genes involved in methylation-dependent chromatin silencing and dopamine signaling, results that reveal new HD therapeutic target pathways. [Display omitted] •Unbiased genome-wide genetic screening in the mouse brain•Identification of in vivo neuronal essential genes•Identification of genetic modifiers of mutant huntingtin toxicity in vivo•Validation of Nme1 as a suppressor of mutant huntingtin toxicity Wertz et al. report a method for unbiased genome-wide genetic screening in the CNS to identify neuronal essential genes in vivo. They also apply this approach to uncover modifiers of mutant huntingtin toxicity in vivo and show that Nme1 expression can modulate Huntington’s disease model phenotypes.