Normal prion protein in Drosophila enhances the toxicity of pathogenic polyglutamine proteins and alters susceptibility to oxidative and autophagy signaling modulators.

To investigate the in vivo functions of normal prion protein (PrP) in Drosophila, we utilized characterized transgenic flies expressing ³(F)⁴-tagged mouse PrP (Mo-PrP³(F)⁴). The neurotoxicity of pathogenic Machado-Joseph Disease (MJD) glutamine (Q) 78 and 127Q proteins were enhanced by the co-expression of Mo-PrP³(F)⁴in the fly eyes, while the eyes of controls flies and flies expressing Mo-PrP³(F)⁴) alone or together with MJD-Q27 or 20Q proteins did not show any defect. Susceptibilities to H₂O₂, paraquat, and Dithiothreitol (DTT) were altered in Mo-PrP³(F)⁴ flies. In addition, Mo-PrP³(F)⁴ flies were significantly more susceptible to the perturbation of autophagy signaling by an autophagy inhibitor, 3-methyladenine (3-MA), and inducer, LiCl. Taken together, our data suggest that Mo-PrP³(F)⁴ may enhance the neurotoxicity of pathogenic Poly-Q proteins by perturbing oxidative and autophagy signaling.