RNA toxicity is a component of ataxin-3 degeneration in Drosophila

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Abstract
Polyglutamine (polyQ) diseases are a class of dominantly inherited neurodegenerative disorders caused by the expansion of a CAG repeat encoding glutamine within the coding region of the respective genes. PolyQ has traditionally been thought to cause neurodegeneration due to protein toxicity. In contrast, pathogenesis in other repeat diseases, such as myotonic dystrophy and fragile X-associated tremor/ataxia syndrome, is thought to result from the expression of toxic RNA repeats. Here they provide evidence that pathogenesis caused by ataxin-3, which contains CAG repeats, also involves an RNA-mediated component. Polyglutamine (polyQ) diseases are a class of dominantly inherited neurodegenerative disorders caused by the expansion of a CAG repeat encoding glutamine within the coding region of the respective genes. PolyQ has been thought to cause neurodegeneration due to protein toxicity. In contrast, pathogenesis in other repeat diseases, such as myotonic dystrophy, is thought to result from the expression of toxic RNA repeats. Here evidence is provided that pathogenesis caused by ataxin-3, which contains CAG repeats, also involves an RNA-mediated component. Polyglutamine (polyQ) diseases are a class of dominantly inherited neurodegenerative disorders caused by the expansion of a CAG repeat encoding glutamine within the coding region of the respective genes1. The molecular and cellular pathways underlying polyQ-induced neurodegeneration are the focus of much research, and it is widely considered that toxic activities of the protein, resulting from the abnormally long polyQ tract, cause pathogenesis2,3. Here we provide evidence for a pathogenic role of the CAG repeat RNA in polyQ toxicity using Drosophila. In a Drosophila screen for modifiers of polyQ degeneration induced by the spinocerebellar ataxia type 3 (SCA3) protein ataxin-3, we isolated an upregulation allele of muscleblind (mbl), a gene implicated in the RNA toxicity of CUG expansion diseases4,5,6. Further analysis indicated that there may be a toxic role of the RNA in polyQ-induced degeneration. We tested the role of the RNA by altering the CAG repeat sequence to an interrupted CAACAG repeat within the polyQ-encoding region; this dramatically mitigated toxicity. In addition, expression of an untranslated CAG repeat of pathogenic length conferred neuronal degeneration. These studies reveal a role for the RNA in polyQ toxicity, highlighting common components in RNA-based and polyQ-protein-based trinucleotide repeat expansion diseases.