Perturbation of protein homeostasis and aggregation of misfolded proteins is a major cause of many human diseases. A hallmark of the neurodegerative disease spinocerebellar ataxia type 7 (SCA7) is given by the intranuclear accumulation of mutant, misfolded ataxin-7 (polyQ-ATXN7). Here we show that endogenous ATXN7 is modified by SUMO, thus also suggesting a physiological role for this modification under conditions of proteotoxic stress caused by the accumulation of misfolded ATXN7. Co-immunoprecipitation experiments, immunofluorescence microscopy and proximity ligation assays confirmed co-localization and interaction of polyQ-ATXN7 with SUMO2 in cells. Moreover, upon inhibition of the proteasome, both endogenous SUMO2/3 and the RNF4 ubiquitin ligase surround large polyQ-ATXN7 intranuclear inclusions. Over-expression of RNF4 and/or SUMO2 significantly decreased levels of polyQ-ATXN7 and, upon proteasomal inhibition, led to a marked increase in the polyubiquitination of polyQ-ATXN7. This provides a mechanism for the clearance of polyQ-ATXN7 from affected cells that involves the recruitment of RNF4 by SUMO2/3-modified polyQ-ATXN7, thus leading to its ubiquitination and proteasomal degradation. In a SCA7 knock-in mouse model we similarly observed colocalization of SUMO2/3 with polyQ-ATXN7 inclusions in cerebellum and retina. Furthermore, we detected accumulation of SUMO2/3 high molecular weight species in cerebellum of SCA7 knock-in mice compared to their wild-type littermates and changes in SUMO-related transcripts. Immunohistochemical analysis showed the accumulation of SUMO proteins and RNF4 in the cerebellum of SCA7 patients. Taken together, our results show that the SUMO pathway contributes to the clearance of aggregated ATXN7 and suggest that its deregulation may be associated with SCA7 disease progression.