December 2002
Volume 43, Issue 13
Free
ARVO Annual Meeting Abstract  |   December 2002
Poly-Q Mediated Interaction of Ataxin-7 and CRX Interferes with Photoreceptor Gene Expression: A Molecular Mechanism for Retinal Degeneration in SCA7
Author Affiliations & Notes
  • S Chen
    Ophthalmology and Visual Sciences Washington University School of Medicine St Louis MO
  • G Peng
    Ophthalmology and Visual Sciences Washington University School of Medicine St Louis MO
  • X Wang
    Ophthalmology and Visual Sciences Washington University School of Medicine St Louis MO
  • LY Li
    Ophthalmology and Visual Sciences Washington University School of Medicine St Louis MO
  • S Xu
    Ophthalmology and Visual Sciences Washington University School of Medicine St Louis MO
  • BL Sopher
    Laboratory Medicine University of Washington Medical Center Seattle WA
  • AR La Spada
    Laboratory Medicine University of Washington Medical Center Seattle WA
  • Footnotes
    Commercial Relationships   S. Chen, None; G. Peng, None; X. Wang, None; L.Y. Li, None; S. Xu, None; B.L. Sopher, None; A.R. La Spada, None. Grant Identification: NIH-EY12543, RPB, Fight for Sight
Investigative Ophthalmology & Visual Science December 2002, Vol.43, 1376. doi:
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    • Get Citation

      S Chen, G Peng, X Wang, LY Li, S Xu, BL Sopher, AR La Spada; Poly-Q Mediated Interaction of Ataxin-7 and CRX Interferes with Photoreceptor Gene Expression: A Molecular Mechanism for Retinal Degeneration in SCA7 . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1376.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Abstract: : Purpose: Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant poly-glutamine(Q) repeat disease characterized by a cone-rod dystrophy type of retinal degeneration. After developing a mouse model of SCA7, we demonstrated that photoreceptor degeneration of SCA7 results from the physical interaction of the poly-Q-expanded disease protein, ataxin-7, with the photoreceptor transcription factor CRX. This interaction interferes with CRX-dependent transcription activation of photoreceptor genes (Neuron, 31:913, 2001). The goal of the present study is to identify the domains of ataxin-7 and CRX that are important for their physical and functional interaction. Methods: Yeast two-hybrid and in vitro co-immunoprecipitation assays were employed to assess the effect of N- and C-terminal deletions of ataxin-7 and CRX upon their physical interaction. Transient co-transfection assays in HEK293T cells with a rhodopsin-luciferase reporter were used to gauge the ability of ataxin-7 deletions to repress CRX transactivation activity. Results: CRX deletions lacking the Q-rich region failed to interact with ataxin-7. Removing 7 out of 9 Q residues of CRX resulted in a CRX protein partially resistant to ataxin-7 mediated repression. Similarly, deleting the poly-Q repeat of ataxin-7 abolished the ataxin-7 - CRX interaction. Quantitative yeast two-hybrid assays demonstrated that the interaction strength of ataxin-7 and CRX is significantly enhanced when the length of the poly-Q tract of ataxin-7 increases from normal to disease-causing status. In addition, deleting the nuclear localization signal sequence from the poly-Q-expanded ataxin-7 reduced its potency to repress CRX. Conclusions: The physical and functional interaction of ataxin-7 with CRX depends upon the poly-Q or Q-rich region of each protein. The nuclear localization of ataxin-7 appears to be required for its role as a transcriptional repressor. Our results further support the view that antagonizing CRX function by expansion of the poly-Q tract in ataxin-7 is responsible for the cone-rod dystrophy phenotype of SCA7.

Keywords: 605 transcription factors • 385 degenerations/dystrophies • 528 proteins encoded by disease genes 
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