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

Mallik, Moushami ; Lakhotia, Subhash C. (2009) RNAi for the large non-coding hsrω transcripts suppresses polyglutamine pathogenesis in Drosophila models RNA Biology, 6 (4). pp. 464-478. ISSN 1547-6286

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Official URL: http://www.landesbioscience.com/journals/rnabiolog...

Related URL: http://dx.doi.org/10.4161/rna.6.4.9268

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.

Item Type:Article
Source:Copyright of this article belongs to Landes Bioscience.
Keywords:Non-coding RNA; hnRNP; PolyQ; CBP; Huntingtin; SCA; Neurodegeneration
ID Code:75942
Deposited On:28 Dec 2011 08:04
Last Modified:28 Dec 2011 08:13

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