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.
Bibliographical noteFunding Information:
We are grateful to Drs. S.H. Orkin (Boston), P. Kazemi-Esfarjani (New York), and I.G. Sharina (Houston) for the generous gifts of the Gfi-1 mutant mice, the UAS-127Q lines, and the BE-2 neuroblastoma cell line; Dr. R. Atkinson for advice and assistance with confocal microscopy; Y. Zhou, Y. He, B. Antalffy, R. Richman, and D. Kang for technical assistance; M. Acar for help with the yeast two-hybrid screen; I. Al-Ramahi and J. Branco for assistance with fly lines; and members of the Zoghbi, Bellen, and Botas labs for helpful discussions and comments on the manuscript. This research was supported by NIH grants NS27699 and Baylor MRRC HD24064 (H.Y.Z.), NS42179 (J.B.), NS22920 (H.T.O.), the Confocal Microscopy Core of BCM MRDDRC (HD024064), Uehara Memorial Foundation Fellowship to H.T., an AMA seed grant to A.J.P., and a NASA grant to H.J.B. H.Y.Z. and H.J.B are HHMI investigators. H.J.-N. was supported by HHMI and NIH Medical Genetics Research Fellowship Program grant T32-GMO7526.