The AXH Domain of Ataxin-1 Mediates Neurodegeneration through Its Interaction with Gfi-1/Senseless Proteins

• Published in: Cell 2005-08, Vol.122 (4), p.633-644
• Main Authors: Tsuda, Hiroshi, Jafar-Nejad, Hamed, Patel, Akash J., Sun, Yaling, Chen, Hung-Kai, Rose, Matthew F., Venken, Koen J.T., Botas, Juan, Orr, Harry T., Bellen, Hugo J., Zoghbi, Huda Y.
• Format: Article
• Language: English
• Subjects: Animals; Ataxin-1; Ataxins; Cells, Cultured; Cerebellum - abnormalities; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Down-Regulation - physiology; Drosophila; Drosophila melanogaster - cytology; Drosophila melanogaster - embryology; Drosophila melanogaster - growth & development; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Mice; Mice, Transgenic; Nerve Degeneration - genetics; Nerve Degeneration - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nervous System - cytology; Nervous System - embryology; Nervous System - growth & development; Nervous System Malformations - genetics; Nervous System Malformations - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Protein Structure, Tertiary - physiology; Purkinje Cells - metabolism; Purkinje Cells - pathology; Spinocerebellar Ataxias - genetics; Spinocerebellar Ataxias - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2005.06.012

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by an expanded glutamine tract in human Ataxin-1 (hAtx-1). The expansion stabilizes hAtx-1, leading to its accumulation. To understand how stabilized hAtx-1 induces selective neuronal degeneration, we studied Drosophila Atx-1 (dAtx-1), which has a conserved AXH domain but lacks a polyglutamine tract. Overexpression of hAtx-1 in fruit flies produces phenotypes similar to those of dAtx-1 but different from the polyglutamine peptide alone. We show that the Drosophila and mammalian transcription factors Senseless/Gfi-1 interact with Atx-1’s AXH domain. In flies, overexpression of Atx-1 inhibits sensory-organ development by decreasing Senseless protein. Similarly, overexpression of wild-type and glutamine-expanded hAtx-1 reduces Gfi-1 levels in Purkinje cells. Deletion of the AXH domain abolishes the effects of glutamine-expanded hAtx-1 on Senseless/Gfi-1. Interestingly, loss of Gfi-1 mimics SCA1 phenotypes in Purkinje cells. These results indicate that the Atx-1/Gfi-1 interaction contributes to the selective Purkinje cell degeneration in SCA1.