The pathogenesis of certain polyQ disorders including HD, SBMA, and SCA3, are likely related to proteolytic cleavage resulting in production of toxic polyQ-containing fragments. It is worth noting though that proteolytic cleavage is possibly not a critical step in all polyQ diseases pathogenesis. Indeed, for polyQ protein normally localized in the cytoplasm, such as htt, ataxin-3, or atrophin-1, proteolysis would facilitate their translocation into nucleus thus increasing their toxicities, while for proteins already localized in the nucleus, such as TATAbinding protein or ataxin-7, proteolytic cleavage may not play a role.