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Identification of genes that modify ataxin-1-induced neurodegeneration


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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Figure 1: Strong (ataxin-1 82Q) and weak (ataxin-1 30Q) eye phenotypes produced by SCA1 overexpression.
Figure 2: Ataxin-1 82Q and high levels of ataxin-1 30Q cause similar phenotypes, in both Drosophila and mice.
Figure 3: Expression of ataxin-1 82Q in Drosophila interneurons causes progressive degeneration.
Figure 4: Modifiers of ataxin-1 82Q neurodegeneration in the protein folding/heat-shock response and ubiquitin proteolytic pathways.
Figure 5: Suppressors and enhancers of ataxin-1 82Q neurodegeneration in new pathways.

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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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Correspondence to Juan Botas.

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Fernandez-Funez, P., Nino-Rosales, M., de Gouyon, B. et al. Identification of genes that modify ataxin-1-induced neurodegeneration . Nature 408, 101–106 (2000).

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