Spinocerebellar ataxia type l - Modeling the pathogenesis of a polyglutamine neurodegenerative disorder in transgenic mice

Spinocerebellar ataxia type 1 (SCA1) is one of a group of dominantly inheri ted neurodegenerative diseases caused by a mutant expansion of a polyglutam ine-repeated sequence within the affected gene. One of the major cell types affected by the gene (ataxin-1) mutation in SCA1 is the cerebellar Purkinj e cell. Targeted expression of mutant ataxin-1 in Purkinje cells of transge nic mice produces an ataxic phenotype with pathological similarities to the human disease. Other transgenic experiments using altered forms of mutant ataxin-1 have shown that nuclear localization of the mutant protein is nece ssary for pathogenesis and that nuclear aggregates of ubiquitinated mutant protein, while a feature of SCA1 and other polyglutamine diseases, are not a requirement for pathogenesis in transgenic models of SCA1. Present and fu ture generations of transgenic mouse models of SCA1 will be valuable tools to further address mechanisms of pathogenesis in polyglutamine-related diso rders.