RNAi for the large non-coding hsromega transcripts suppresses polyglutamine pathogenesis in Drosophila models.
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 hsromega transcripts has been shown to dominantly enhance polyQ induced cytotoxicity in Drosophila. In the present study we demonstrate that RNA interference mediated downregulation of hsromega-n transcripts is sufficient to suppress pathogenesis in several Drosophila models of human polyQ neurodegenerative diseases. Loss of hsromega-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 hsromega-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 hsromega-n RNAi also abolishes the induction of Hsp70. These results suggest that the hsromega transcripts have a role in early stages of polyQ aggregate formation. Interestingly, hsromega-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 hsromega transcripts in human thus appear to be promising candidates as therapeutic targets for the polyQ-mediated neurodegenerative diseases.
Mallik
Moushami
M
Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, India.
Lakhotia
Subhash C
SC
D000483:Alleles; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics*; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics*; D005123:Eye / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D009420:Nervous System / Q000187:drug effects / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000473:pathology*; D010455:Peptides / Q000633:toxicity*; D020836:Protein Structure, Quaternary; D034622:RNA Interference / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D022661:RNA, Untranslated / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D019076:Transgenes / Q000235:genetics
D029721:Drosophila Proteins; D010455:Peptides; D012333:RNA, Messenger; D022661:RNA, Untranslated; C097188:polyglutamine