The AXH domain of Ataxin-1 mediates neurodegeneration through its interaction with Gfi-1/Senseless proteins

Cell. 2005 Aug 26;122(4):633-44. doi: 10.1016/j.cell.2005.06.012.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Ataxin-1
  • Ataxins
  • Cells, Cultured
  • Cerebellum / abnormalities
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Down-Regulation / physiology
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / cytology
  • Drosophila melanogaster / embryology*
  • Drosophila melanogaster / growth & development
  • 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*

Substances

  • ATXN1 protein, human
  • Ataxin-1
  • Ataxins
  • Atxn1 protein, mouse
  • DNA-Binding Proteins
  • Drosophila Proteins
  • Gfi1 protein, mouse
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Transcription Factors
  • sens protein, Drosophila