Genome-wide CNS Screening in Mouse Models of Huntington's Disease

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by CAG trinucleotide repeat expansions in the huntingtin gene. There is no cure or effective therapeutic for HD, and the molecular mechanisms underlying mutant Huntingtin protein (mHTT) toxicity are not fully understood. Genetic screening is a powerful approach that has been used to elucidate previously unknown disease mechanisms in various fields. Although genome-wise in vivo genetic screens are routine in some model organisms, and increasingly feasible in mice, to date such screening has not been feasible in the mammalian central nervous system. Here we report the results of the first genome-wide lentiviral shRNA-based knockdown genetic screen in the mammalian CNS, which identifies suppressors of mHTT toxicity in two mouse models of HD.