Perturbation of the Akt/Gsk3-beta signaling pathway is common to Drosophila expressing expanded untranslated CAG, CUG and AUUCU repeat RNAs

Recent evidence supports a role for RNA as a common pathogenic agent in both the polyglutamine and untranslated dominant expanded repeat disorders. One feature of all repeat sequences currently associated with disease is their predicted ability to form a hairpin secondary structure at the RNA level. In order to investigate mechanisms by which hairpin forming repeat RNAs could induce neurodegeneration, we have looked for alterations in gene transcripts as hallmarks of the cellular response to toxic hairpin repeat RNAs. Three disease associated repeat sequences - CAG, CUG and AUUCU - were specifically expressed in the neurons of Drosophila and resultant common, early, transcriptional changes assessed by microarray analyses. Transcripts that encode several components of the Akt/Gsk3- signalling pathway were altered as a consequence of expression of these repeat RNAs, indicating that this pathway is a component of the neuronal response to these pathogenic RNAs and may represent an important common therapeutic target in this class of diseases.

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van Eyk CL, O'Keefe LV, Lawlor KT, Samaraweera SE, McLeod CJ, Price GR, Venter DJ, Richards RI