ATAXIN-1 NUCLEAR-LOCALIZATION AND AGGREGATION - ROLE IN POLYGLUTAMINE-INDUCED DISEASE IN SCA1 TRANSGENIC MICE

Transgenic mice carrying the spinocerebellar ataxia type 1 (SCA1) gene , a polyglutamine neurodegenerative disorder, develop ataxia with atax in-l localized to aggregates within cerebellar Purkinje cells nuclei. To examine the importance of nuclear localization and aggregation in p athogenesis, mice expressing ataxin-1[82] with a mutated NLS were esta blished. These mice did not develop disease, demonstrating that nuclea r localization is critical for pathogenesis. In a second series of tra nsgenic mice, ataxin-1[77] containing a deletion within the self-assoc iation region was expressed within Purkinje cells nuclei. These mice d eveloped ataxia and Purkinje cell pathology similar to the original SC A1 mice. However, no evidence of nuclear ataxin-l aggregates was found . Thus, although nuclear localization of ataxin-1 is necessary, nuclea r aggregation of ataxin-l is not required to initiate pathogenesis in transgenic mice.