Abstract
Dietary copper is essential for multicellular organisms. Copper is redox active and required as a cofactor for enzymes such as the antioxidant Superoxide Dismutase 1 (SOD1). Copper dyshomeostasis has been implicated in Alzheimer’s disease. Mutations in the presenilin genes encoding PS1 and PS2 are major causes of early-onset familial Alzheimer’s disease. PS1 and PS2 are required for efficient copper uptake in mammalian systems. Here we demonstrate a conserved role for presenilin in dietary copper uptake in the fly Drosophila melanogaster. Ubiquitous RNA interference-mediated knockdown of the single Drosophila presenilin (PSN) gene is lethal. However, PSN knockdown in the midgut produces viable flies. These flies have reduced copper levels and are more tolerant to excess dietary copper. Expression of a copper-responsive EYFP construct was also lower in the midgut of these larvae, indicative of reduced dietary copper uptake. SOD activity was reduced by midgut PSN knockdown, and these flies were sensitive to the superoxide-inducing chemical paraquat. These data support presenilin being needed for dietary copper uptake in the gut and so impacting on SOD activity and tolerance to oxidative stress. These results are consistent with previous studies of mammalian presenilins, supporting a conserved role for these proteins in mediating copper uptake.
Highlights
Presenilins are evolutionarily conserved proteins that function as the catalytic subunit of the c-secretase multi-protein complex [1,2]. c-secretase functions in the intramembrane proteolysis of many substrates involved in diverse cellular processes including Notch, which has a well-characterized role in cell differentiation and development in diverse organisms including flies (Drosophila melanogaster) and mammals [2,3]
Drosophila media was supplemented with additional copper (CuSO4, Sigma) or zinc (ZnSO4, Sigma) at concentrations indicated in figure legends. 0.5 mM bathocuproine disulfonic acid (BCS; Sigma) and 0.1 mM N,N,N,N-tetrakis(2pyridylmethyl)ethylenediamine (TPEN, Sigma) were added to media to limit available copper and zinc respectively. 10 mM paraquat (Sigma) was used to induce superoxide
The well-established UAS-GAL4 system was used for RNAimediated knockdown of PSN expression to determine whether presenilin contributes to metal homeostasis in Drosophila
Summary
Presenilins are evolutionarily conserved proteins that function as the catalytic subunit of the c-secretase multi-protein complex [1,2]. c-secretase functions in the intramembrane proteolysis of many substrates involved in diverse cellular processes including Notch, which has a well-characterized role in cell differentiation and development in diverse organisms including flies (Drosophila melanogaster) and mammals [2,3]. C-secretase functions in the intramembrane proteolysis of many substrates involved in diverse cellular processes including Notch, which has a well-characterized role in cell differentiation and development in diverse organisms including flies (Drosophila melanogaster) and mammals [2,3]. Our research groups demonstrated a novel role for PS1 and PS2 in regulating uptake of copper and zinc in mammalian systems [4]. Copper is a redox active metal required by numerous proteins including Superoxide Dismutase 1 (SOD1), an important cellular antioxidant [6,7]. Zinc is structurally important for many proteins, including SOD1 [6,8]. The uptake, sequestration, distribution and efflux of copper and zinc, must be regulated at the cellular level and in the organism as a whole
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