Drosophila as a Model for Neurodegenerative Disease: Roles of RNA Pathways in Pathogenesis

Abstract

Human neurodegenerative diseases, including the polyglutamine diseases like Huntington's disease and Spinocerebellar ataxia type 3, are late-onset progressive neurodegenerative disorders for which few cures or treatments are available. To develop new approaches to the understanding of and foundation for therapeutics for these diseases, we are using Drosophila as a model. In these studies, we have expressed the human disease gene for the polyglutamine disorder Spinocerebellar ataxia type 3 in flies. Expression of a normal, non-mutant protein with a short polyglutamine stretch has no effect, but expression of a disease form of the protein with an expanded polyglutamine confers late-onset progressive neurodegeneration.

Our research has subsequently focused on modifier screens for genes that modulate the neurodegeneration. These genetic screens have confirmed our earlier findings that modulation of protein solubility and protein quality control pathways has a dramatic effect on polyglutamine protein toxicity. In our genetic screens, however, we also found evidence of a role for microRNAs in disease and a pathogenic role of the CAG repeat RNA in polyglutamine-induced degeneration. For the microRNA pathway, we found that the microRNA bantam is a dosage-sensitive modifier of polyglutamine toxicity and that compromise of the entire microRNA pathway is more severely deleterious. In other screens, we isolated the gene muscleblind as an upregulation enhancer of polyglutamine protein toxicity. This finding suggested to us that there might be a role for the CAG-expanded repeat RNA in polyglutamine degeneration because muscleblind is a known modulator of CUG-based RNA diseases. We further tested the role of the RNA in polyglutamine toxicity by altering the CAG repeat sequence to an interrupted CAA/CAG repeat within the polyglutamine-encoding region; this alteration mitigated toxicity. We further found that expression of an untranslated CAG repeat of pathogenic length confered neural dysfunction and degeneration. These studies indicate that a number of different RNA pathways modulate polyglutamine disease and neurodegeneration, including microRNA pathways and, for CAG repeat diseases, the RNA itself. This latter finding highlights common components between RNA-based and polyglutamine protein-based repeat expansion diseases.