Identification of genes that modify ataxin-1-induced neurodegeneration

Pedro Fernandez-Funez, Maria Laura Nino-Rosales, Beatrice de Gouyon, Wei-Chi She, James M. Luchak, Pedro Martinez, Enrique Turiegano, Jonathan Benito, Maria Capovilla, Pamela J. Skinner, Alanna McCall, Inmaculada Canal, Harry T. Orr, Huda Y. Zoghbi and Juan Botas ()
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Pedro Fernandez-Funez: Department of Molecular and Human Genetics
Maria Laura Nino-Rosales: Department of Molecular and Human Genetics
Beatrice de Gouyon: Department of Molecular and Human Genetics
Wei-Chi She: Department of Molecular and Human Genetics
James M. Luchak: Department of Molecular and Human Genetics
Pedro Martinez: Department of Molecular and Human Genetics
Enrique Turiegano: Universidad Autonoma de Madrid
Jonathan Benito: Universidad Autonoma de Madrid
Maria Capovilla: Department of Molecular and Human Genetics
Pamela J. Skinner: Institute of Human Genetics, University of Minnesota
Alanna McCall: Department of Molecular and Human Genetics
Inmaculada Canal: Universidad Autonoma de Madrid
Harry T. Orr: Institute of Human Genetics, University of Minnesota
Huda Y. Zoghbi: Department of Molecular and Human Genetics
Juan Botas: Department of Molecular and Human Genetics

Nature, 2000, vol. 408, issue 6808, 101-106

Abstract: Abstract 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.

Date: 2000
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DOI: 10.1038/35040584

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