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 3F4-tagged mouse PrP (Mo-PrP3F4). The neurotoxicity of pathogenic Machado-Joseph Disease (MJD) glutamine (Q) 78 and 127Q proteins were enhanced by the co-expression of Mo-PrP3F4 in the fly eyes, while the eyes of controls flies and flies expressing Mo-PrP3F4 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-PrP3F4 flies. In addition, Mo-PrP3F4 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-PrP3F4 may enhance the neurotoxicity of pathogenic Poly-Q proteins by perturbing oxidative and autophagy signaling.

Research highlights
► We investigated the in vivo function of wild-type PrP by expressing 3F4-tagged mouse PrP (Mo-PrP3F4) in Drosophila.
► The neurotoxic effects of MJD-Q78 and 127Q proteins in Drosophila eyes were enhanced by Mo-PrP3F4.
► Mo-PrP3F4 flies showed altered susceptibility to oxidative stressors.
► Mo-PrP3F4 flies showed increased susceptibility to an autophagy inhibitor, 3-MA, and inducer, LiCl.
► Our data suggest that the Mo-PrP3F4-induced perturbation of oxidative and autophagy signaling may be the basis of enhanced Poly-Q protein neurotoxicity in Drosophila.