A growing number of human neurodegenerative diseases result from the expansion of a glutamine repeat in the protein that causes the disease1. Spinocerebellar ataxia type 1 (SCA1) is one such disease—caused by expansion of a polyglutamine tract in the protein ataxin-1. To elucidate the genetic pathways and molecular mechanisms underlying neuronal degeneration in this group of diseases, we have created a model system for SCA1 by expressing the full-length human SCA1 gene in Drosophila. Here we show that high levels of wild-type ataxin-1 can cause degenerative phenotypes similar to those caused by the expanded protein. We conducted genetic screens to identify genes that modify SCA1-induced neurodegeneration. Several modifiers highlight the role of protein folding and protein clearance in the development of SCA1. Furthermore, new mechanisms of polyglutamine pathogenesis were revealed by the discovery of modifiers that are involved in RNA processing, transcriptional regulation and cellular detoxification. These findings may be relevant to the treatment of polyglutamine diseases and, perhaps, to other neurodegenerative diseases, such as Alzheimer's and Parkinson's disease.

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We thank M. Mancini for help with the confocal microscope; K.-W. Choi and members of his laboratory for help with the eye sections; C. Cummings for advice and insightful discussions; V. Brandt for editorial help; M. Magarinos and P. Herrero for help with the initial fly screens; R. Davis and A. L. Beaudet for reading the manuscript; C. Cater, G. Rubin, D. Cribbs, R. Davis, T. Aigaki, H. Steller, G. Pennetta, S. Parkhurst and the Bloomington Stock Center for fly strains; and M. Levine and R. Wharton for antibodies. This work was supported by a grant of the NIH to J.B. J.B. is also grateful for initial support by the Banco Bilbao Vizcaya. M.L.N.-R. was supported by an HHMI postdoctoral fellowship for physicians. H.Y.Z. is a Howard Hughes Medical Institute Investigator.

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  1. Pedro Fernandez-Funez, Maria Laura Nino-Rosales and Huda Y. Zoghbi: These authors contributed equally to this work


  1. Department of Molecular and Human Genetics

    • Pedro Fernandez-Funez
    • , Maria Laura Nino-Rosales
    • , Beatrice de Gouyon
    • , Wei-Chi She
    • , James M. Luchak
    • , Pedro Martinez
    • , Maria Capovilla
    • , Alanna McCall
    • , Huda Y. Zoghbi
    •  & Juan Botas
  2. Department of Pediatrics

    • Huda Y. Zoghbi
  3. Program in Developmental Biology

    • Wei-Chi She
    • , Huda Y. Zoghbi
    •  & Juan Botas
  4. Howard Hughes Medical Institute, Baylor College of Medicine, Houston, 77030, Texas, USA

    • Huda Y. Zoghbi
  5. Departamento de Biologia, Universidad Autonoma de Madrid, Madrid, 28049, Spain

    • Enrique Turiegano
    • , Jonathan Benito
    •  & Inmaculada Canal
  6. Institute of Human Genetics, University of Minnesota, Minneapolis, 55455 , Minnesota, USA

    • Pamela J. Skinner
    •  & Harry T. Orr


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