title: The AXH domain of Ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/Senseless proteins.
abstract: 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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuda
authors.forename: Hamed
authors.initials: H
authors.lastname: Jafar-Nejad
authors.forename: Akash J
authors.initials: AJ
authors.lastname: Patel
authors.forename: Yaling
authors.initials: Y
authors.lastname: Sun
authors.forename: Hung-Kai
authors.initials: HK
authors.lastname: Chen
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Rose
authors.forename: Koen J T
authors.initials: KJ
authors.lastname: Venken
authors.forename: Juan
authors.initials: J
authors.lastname: Botas
authors.forename: Harry T
authors.initials: HT
authors.lastname: Orr
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Bellen
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
mesh_terms: D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D002478:Cells, Cultured; D002531:Cerebellum / Q000002:abnormalities; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000196:embryology* / Q000254:growth & development; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009420:Nervous System / Q000166:cytology / Q000196:embryology* / Q000254:growth & development; D009421:Nervous System Malformations / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C079873:Gfi1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C413162:sens protein, Drosophila