The expression of ataxin-1 causes cell death in the Drosphila eye. Wild-type eye, left; eye expressing wild-type ataxin-1, middle; eye expressing mutant ataxin-1, right. Adapted, with permission, from Nature 408, 101–106 (2000) © Macmillan Magazines Ltd.

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder caused by the expansion of a glutamine tract in the protein ataxin-1. As for other polyglutamine disorders, the involvement of the mutant protein in pathogenesis is beyond doubt. What is much less clear, however, is the mechanism by which the polyglutamine tract expansion leads to neuronal death. Although aggregation of ataxin-1 seems to be an initial step, the events downstream of aggregation are unknown, curtailing our chances to develop strategies to prevent cell death. Now, Fernandez-Funez et al. have taken an initial look at the factors capable of modifying ataxin-1-induced neurodegeneration by creating transgenic flies that express the human version of the mutant, full-length protein.

The expression of mutant ataxin-1 in the eye or in the ventral nerve cord of transgenic flies caused progressive cell degeneration and was accompanied by the presence of cellular inclusions analogous to those found in SCA1. This observation allowed the authors to conduct a genetic screen to identify genes capable of suppressing or enhancing the phenotype of the mutant flies. Among the genes they identified, some belonged to pathways already implicated in polyglutamine-induced neurodegeneration, such as the ubiquitin and the protein-folding pathways, further highlighting the strength of the approach.

More importantly, the screen led Fernandez-Funez et al. to find genes from pathways not previously known to participate in cell death, which could actually suppress the ataxin-1-induced phenotype. One of these genes caused the overproduction of glutathione-S-transferase, an enzyme involved in the cellular response to oxidative stress. A second gene was associated with the overexpression of a protein analogous to known components of the nuclear pore, an intriguing finding considering the nuclear accumulation of ataxin-1 aggregates. A third suppressor gene encoded a transcriptional cofactor and, in fact, the screen revealed some other transcriptional cofactors that have the opposite effect and actually exacerbate the phenotype, indicating that alterations in RNA processing may be involved in the degenerative process.

The unexpected observation that the wild-type form of ataxin-1, which is innocuous in humans, caused mild degeneration in transgenic flies could be related to the actual protein levels found in the cells of the different organisms. Alternatively, it could be the manifestation of differences between fly and human in the cellular context in which ataxin-1 is expressed. Although these putative differences would need to be characterized to define the actual potential of this new animal model, the identification of new downstream pathways involved in neurodegeneration opens the door to developing treatments not against the disease trigger, but aimed to lessen the cytotoxic effects of the pathology and slow the decline caused by the polyglutamine disorders.