Ataxin-1 Nuclear Localization and Aggregation: Role in Polyglutamine-Induced Disease in SCA1 Transgenic Mice

• Published in: Cell 1998-10, Vol.95 (1), p.41-53
• Main Authors: Klement, Ivan A, Skinner, Pamela J, Kaytor, Michael D, Yi, Hong, Hersch, Steven M, Clark, H.Brent, Zoghbi, Huda Y, Orr, Harry T
• Format: Article
• Language: English
• Subjects: Animals; Ataxia - chemically induced; Ataxia - metabolism; Ataxin-1; Ataxins; Cell Nucleus - metabolism; COS Cells; Cytoplasm - metabolism; Mice; Mice, Transgenic; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - physiology; Neurodegenerative Diseases - etiology; Nuclear Localization Signals - genetics; Nuclear Localization Signals - physiology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nuclear Proteins - physiology; Peptides; Purkinje Cells - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(00)81781-X

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[82] 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[77] 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.