Although various RNA-processing proteins are implicated in neurodegenerative mechanisms, there is no firm evidence that defective RNA splicing causes neuronal loss. The pre-messenger RNA splicing machinery includes several uridine-rich small nuclear RNAs (U-snRNAs). Here, Jia et al. show that in mice, a mutation in Rnu2-8, which is one of several U2 snRNA genes, causes progressive neurodegeneration and ataxia. This neuronal loss follows a distinct spatiotemporal pattern and is associated with defects in alternative splicing. Thus, impaired RNA processing and, specifically, mutations in U-snRNA genes can have profound effects on neuronal viability.