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Understanding the molecular basis of neurodegenerative diseases (NDDs), and how they interact with the aging process, is one of the greatest challenges in neuroscience. As the most common NDDs, including Alzheimer’s, Parkinson’s, and Huntington’s diseases remain essentially without a cure, the search for therapeutic targets becomes imperative. We have developed a novel platform for the study of NDDs, utilizing the disease-relevant cellular populations in their natural environment. For these screens, which we term SLIC (Synthetic Lethal In the Central nervous system), pooled libraries of lentivirus for knock-down, knock-out, or over-expression of all known genes in the genome are injected into the relevant disease regions in the mouse brain, with one barcoded virus infecting one cell. Comparison, by genomic sequencing, of lentiviruses that are retrieved from wild-type animals, but not from disease model littermates, after various times of incubation in the mouse brain, reveals target genes that function as enhancers of toxicity specific to the disease-associated mutation. We have implemented SLIC for the study of Huntington’s disease, which is the most common inherited NDD caused by abnormal CAG expansion in the Huntingtin gene. We identified the age-regulated glutathione peroxidase 6 (Gpx6) 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.