A genetic screen for suppressors of neuron degeneration in a C. elegans sod-1G85R model of Amyotrophic Lateral Sclerosis

Abstract

Genetic variants in superoxide dismutase 1 (SOD1) cause the progressive neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). Treatments for this disease are limited, and the unique vulnerability of cholinergic and glutamatergic motor neurons to degeneration seen in ALS patients is not clearly understood. Identifying genetic modifiers of neurodegeneration can provide insight into the selective vulnerability of motor neurons in ALS and may accelerate identification of novel therapeutic targets. Here, we describe a forward genetic screen for suppressors of the stress-induced glutamatergic neuron degeneration in a single-copy C. elegans model of sod-1G85R. Used two different screening strategies, we identified 53 suppressor lines that decreased glutamatergic neuron degeneration to varying degrees. To rapidly identify suppressor genes, we sequenced suppressor lines and identified candidate suppressor genes based on frequency of de novo exonic mutations and previously published work. Two candidates were tested and excluded as suppressor genes: erh-1 and imph-1. For a subset of unidentified suppressor lines, we determined if cholinergic neurodegeneration was also suppressed; roughly one-third of suppressor lines showed no corresponding cholinergic neuron rescue, suggesting that mechanisms involved in cholinergic and glutamatergic degeneration are at least partially divergent. This study outlines the first unbiased genetic screen in a knock-in model of SOD1 neurodegeneration, describes a cohort of candidate suppressor lines with decreased SOD1-dependent neurodegeneration, excludes two candidates and discusses approaches for suppressor mutation isolation and gene identification.