In order to get insight into the biological function of ataxin-3 and the pathogenesis of spinocerebellar ataxia type 3 and Machado-Joseph disease (SCA3/MJD) , a yeast two-hybrid technology was carried out to screen the adult brain cDNA library using the full-length polyglutamine-expanded ataxin-3 as bait . Small ubiquitin-like modifier 1(SUMO-1) was identified as a novel ataxin-3-interacting protein. Subsequently, co-immunoprecipitation showed that both the wild-type ataxin-3 and the polyglutamine-expanded ataxin-3 were covalently modified by SUMO-1 in SH-SY5Y cell; immunofluorescence showed that the intranuclear aggregates formatted by the polyglutamine-expanded ataxin-3 co-localized with SUMO-1. Taken together, the data suggest that the biological function of ataxin-3 may be regulated by SUMO-1, and that SUMO-1 may participate in the pathogenesis of SCA3/MJD.