Altered expression of the noncoding hsrω gene enhances poly-Q induced neurotoxicity in Drosophila

Abstract

In an earlier report two P-transposon insertion alleles of the noncoding hsrω gene, hsrω⁰⁵²⁴¹ and P292 were shown to enhance neurodegeneration caused by expression of ataxin-1 protein with expanded poly-Q in a Drosophila model. In present study, we examined the possible relation between hsrω gene expression and toxicity due to poly-O pathogenesis. The Drosophila hsrω gene produces several noncoding transcripts in almost all cell types, of which the > 10 kb long hsrω-n transcript organizes heterogeneous RNA binding (hnRNPs) and related proteins as nucleoplasmic omega speckles. We show that P insertion alleles of the hsrm gene, which cause its overexpression, dominantly enhance neurodegenerotion in fly eyes expressin-g either expanded poly-O (127Q) or mutant huntingtin protein. Null allele of Hrb87F gene, encoding hnRNPA1, and a novel gene's mutant allele (I(3)p/10R), which affects the omega speckles, also dominantly enhance 127Q-induced neurodegeneration. The hsrω-n transcripts or the hnRNPs do not colocolize with the poly-Q nuclear inclusion bodies, neither in hsrm wild type, nor in hsrm mutant background. However, the levels of poly-O and Hsp70 were significantly higher in bsro: mutant eye discs. Sequestration of hnRNPs and other related RNA-binding proteins by overexpression of hsrω transcripts in hsrω⁰⁵²⁴¹ or in /(3)p/10^R background or the reduced levels of Hrb87F protein seem to affect nuclear RNA metabolism, thus enhancing the toxicity due to poly-Q expansion.