Abstract
Iron is required for organismal growth. Therefore, limiting iron availability may be a key part of the host’s innate immune response to various pathogens, for example, in Drosophila infected with Zygomycetes. One way the host can transiently reduce iron bioavailability is by ferritin overexpression. To study the effects of neuronal-specific ferritin overexpression on survival and neurodegeneration we generated flies simultaneously over-expressing transgenes for both ferritin subunits in all neurons. We used two independent recombinant chromosomes bearing UAS-Fer1HCH, UAS-Fer2LCH transgenes and obtained qualitatively different levels of late-onset behavioral and lifespan declines. We subsequently discovered that one parental strain had been infected with a virulent form of the bacterial endosymbiont Wolbachia, causing widespread neuronal apoptosis and premature death. This phenotype was exacerbated by ferritin overexpression and was curable by antibiotic treatment. Neuronal ferritin overexpression in uninfected flies did not cause evident neurodegeneration but resulted in a late-onset behavioral decline, as previously reported for ferritin overexpression in glia. The results suggest that ferritin overexpression in the central nervous system of flies is tolerated well in young individuals with adverse manifestations appearing only late in life or under unrelated pathophysiological conditions.
Highlights
Iron is essential for the growth of microorganisms and animals because it serves as a cofactor in many enzymes (Sheftel et al, 2012)
Flies bearing the transgenes alone were used as controls, but we note that UAS-Fer1HCH, UAS-Fer2LCH/+; +/+; +/+ females behaved differently depending on whether their mothers were infected with Wolbachia or not and this observation was unknown to us when experiments were originally planned and performed
The hypothesis that Wolbachia contributes metabolic provisioning to its hosts originated from whole genome sequencing projects showing that the entire heme biosynthesis pathway was present in Wolbachia but absent in Brugia malayi (Foster et al, 2005)
Summary
Iron is essential for the growth of microorganisms and animals because it serves as a cofactor in many enzymes (Sheftel et al, 2012). It is known that iron is normally stored in specialized intestinal cells expressing ferritin within their secretory system (Locke and Leung, 1984; Mehta et al, 2009). Disrupted ferritin function by mutation or RNA interference (RNAi) results in embryonic or first instar larval lethality (Missirlis et al, 2007; Li, 2010; Tang and Zhou, 2013a). Overexpression of ferritin leads to excess iron sequestration and functional iron deficiency, which does not impede development to adulthood (Missirlis et al, 2007; Gutierrez et al, 2013; Tang and Zhou, 2013a). The effects of neuronal ferritin overexpression in otherwise wild type individuals have not been studied to date and were the first objective of this study
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