Ataxin-1 with an expanded glutamine tract induces disease via alterations in nuclear function

Spinocerebelllar ataxia type I (SCA 1 ) i-4 a neurogenetic disorder caused by the expansion of a polyglutamine tract in alaxin !. Kxpression of mutant ataxin 1 in Purkhije cells uf îransgenic mice induces ataxia. In these mice, mutant alaxin-1 has an abnormal nuclear distribution in 1'urkinje cells: Localized to a single lar-4r nuclear inclusion that is ubiguinated. Similar structures are found in neurons of SCA 1 patients. In transferred COS cells, mutant ataxin-1 also demonstrates an unique nuclear distribution compared to wildtype. Moreover, expression of mutant ataxin-1 COS cells causes a specific redistribution of the unclear matrix-associated protein FMI,. Yeast two hybrid studies have determined that ainino acids -195 to (iOô of ataxin-1 function as a self-association region, tutti have identified three other nuclear proteins with which ataxin-1 can interact. These studies suggest that SCAl pathogenesis is due to a disruption of ntulear architecture and/or function by mutant ataxin-l. To examine, this hypothesis directly, we have identified a functional nuclear localization sequence (KKKR) within the COOH termim-4 of ataxin 1. Replacement of K772 with a T blocks transport of afaxin 1 lo the nucleic of Purkinje cells in transgenîc mice. Initial analysis of mice expressing an expanded form of ataxin I with this NI.S mutation indicate that thc-4e mice do no! develop ataxia as seen in mice expressing an expanded form of ataxin-1 having a functional NM.S. Based on lhe,-.e studies a molecular model of SCA 1 pathogenesis will be presented.