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Despite recent advances in our understanding of the physiological importance of SEL1L-HRD1 endoplasmic reticulum (ER)-associated protein degradation (ERAD) using cell type-specific knockout (KO) mouse models, its relevance and importance in ataxia pathogenesis remain unknown. Here we show that loss of SEL1L-HRD1 ERAD complex interaction or function in Purkinje cells leads to cerebellar ataxia. Both homozygous knock-in (KI) mice carryingSEL1Lvariantp.Ser658Pro(S658P) and mice with Purkinje cell-specific deletion of SEL1L exhibit early-onset cerebellar ataxia, although disease severity and progression differ between the models. Structure-function analyses reveal thatSEL1L S658Pvariant impairs, not abolishes, ERAD function by attenuating the interaction between SEL1L and HRD1. Proteomic screen of potential endogenous substrates leads to the identification of Astrotactin 1 and 2, two integral membrane proteins involved in neuronal function and development, whose maturation and biogenesis in the ER depend on SEL1L-HRD1 ERAD activity. These data demonstrate the pathophysiological importance of SEL1L-HRD1 interaction and function in the pathogenesis of cerebellar ataxia.One-sentence summaryDisruption of SEL1L-HRD1 interaction and function causes cerebellar ataxia in mice.