Identification of genes that modify ataxin-1-induced neurodegeneration

A growing number of human neurodegenerative diseases result from the expans ion of a glutamine repeat in the protein that causes the disease(1). Spinoc erebellar ataxia type 1 (SCA1) is one such disease-caused by expansion of a polyglutamine tract in the protein ataxin-1. To elucidate the genetic path ways and molecular mechanisms underlying neuronal degeneration in this grou p of diseases, we have created a model system for SCA1 by expressing the fu ll-length human SCA1 gene in Drosophila. Here we show that high levels of w ild-type ataxin-1 can cause degenerative phenotypes similar to those caused by the expanded protein. We conducted genetic screens to identify genes th at modify SCA1-induced neurodegeneration. Several modifiers highlight the r ole of protein folding and protein clearance in the development of SCA1. Fu rthermore, new mechanisms of polyglutamine pathogenesis were revealed by th e discovery of modifiers that are involved in RNA processing, transcription al regulation and cellular detoxification. These findings may be relevant t o the treatment of polyglutamine diseases and, perhaps, to other neurodegen erative diseases, such as Alzheimer's and Parkinson's disease.