RNAi for the large non-coding hsrω transcripts suppresses polyglutamine pathogenesis in Drosophila models

Abstract

Polyglutamine diseases are a class of inherited neurodegenerative disorders, characterized by expansion of CAG trinucleotide repeats translated into elongated glutamine tracts within the mutant proteins. Overexpression of the non-coding hsrω transcripts has been shown to dominantly enhance polyQ induced cytotoxicity in Drosophila. In the present study we demonstrate that RNA interference mediated downregulation of hsrω-n transcripts is sufficient to suppress pathogenesis in several Drosophila models of human polyQ neurodegenerative diseases. Loss of hsrω-n RNA not only suppresses the eye-specific degeneration mediated by GMR-GAL4 driven expression of the 127Q or MJDtr-Q78 or ataxin1 82Q or httex1p Q93 transgene, but also rescues premature death of flies expressing the expanded polyQ proteins pan-neuronally using the elav-GAL4 driver. We further demonstrate that the morphological and functional rescue of polyQ toxicity observed upon hsrω-n RNAi is associated with substantial reduction of polyQ protein aggregation without affecting transcription of the 127Q transgene. Unlike in the polyQ expressing cells, co-expression of hsrω-n RNAi also abolishes the induction of Hsp70. These results suggest that the hsrω transcripts have a role in early stages of polyQ aggregate formation. Interestingly, hsrω-RNAi has, at best, only a marginal effect on neuropathy following overexpression of normal or mutant tau protein in flies. Functional analogues of the large non-coding hsrω transcripts in human thus appear to be promising candidates as therapeutic targets for the polyQ-mediated neurodegenerative diseases.