Transgenic mice carrying the spinocerebellar ataxia type 1 (SCA1) gene, a polyglutamine neurodegenerative disorder, develop ataxia with ataxin-1 localized to aggregates within cerebellar Purkinje cells nuclei. To examine the importance of nuclear localization and aggregation in pathogenesis, mice expressing ataxin-1 with a mutated NLS were established. These mice did not develop disease, demonstrating that nuclear localization is critical for pathogenesis. In a second series of transgenic mice, ataxin-1  containing a deletion within the self-association region was expressed within Purkinje cells nuclei. These mice developed ataxia and Purkinje cell pathology similar to the original SCA1 mice. However, no evidence of nuclear ataxin-1 aggregates was found. Thus, although nuclear localization of ataxin-1 is necessary, nuclear aggregation of ataxin-1 is not required to initiate pathogenesis in transgenic mice.
Bibliographical noteFunding Information:
We thank R. Ehlenfeldt and B. Pinch for assistance in the production and maintenance of transgenic mice, Dr. Tao Zu and Trevor Copland for technical assistance, and Dr. M. MacDonald (MGH) for providing the 1F8 antibody. This work was supported by grants from the National Institute of Neurological Disease and Stroke, NIH (NS35255, NS27699, and NS22920).