1. The AXH Domain of Ataxin-1 Mediates Neurodegeneration through Its Interaction with Gfi-1/Senseless Proteins
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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., and Zoghbi, Huda Y.
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NEURODEGENERATION , *AMINO acids , *GLUTAMINE , *DROSOPHILA - Abstract
Summary: 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. [Copyright &y& Elsevier]
- Published
- 2005
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