Several neurological disorders, including spinocerebellar ataxia type 1 (SCA1), are caused by a toxic build-up of mutant proteins. To identify targets for SCA1, this study used parallel human cell-based and fruitfly genetic screens to show that downregulation of components of the RAS–MAPK (mitogen-activated protein kinase)–MSK1 (nuclear mitogen- and stress-activated protein kinase 1) pathway decreased mutant ataxin 1 levels and suppressed neurodegeneration in fruitflies and mice. Pharmacological inhibition of the pathway also decreased ataxin 1 levels, which suggests that it is a new target in SCA1. These methods could be used to identify targets for other neurodegenerative disorders with similar pathogenic mechanisms.