DROSOFELA · Identification of novel iron metabolism genes by genetic screening in Drosophila

Identification of novel iron metabolism genes by genetic screening in Drosophila

This project was undertaken in the laboratory of Dr Missirlis in the School of Biological and Chemical Sciences, Queen Mary University of London in the United Kingdom. The grant supported research on the role of metals in biology, using the fruit-fly Drosophila melanogaster as a model system. The project investigated metal transport (see paper published in the Journal of Experimental Biology), regulation of metal homeostasis (see papers in Neurobiology of Disease and Biochimie), and biological interactions between metals (see papers in FEBS Letters and Biometals). One core hypothesis being tested is that metal trafficking is not a passive process, but rather is integrated within animal physiology influencing or even driving metabolic functions. Ongoing investigations on metal homeostasis in circadian clocks (manuscript in preparation), in development and in fly models of human disease use a number of different experimental approaches and exploit available resources for Drosophila research. The project involved two genetic screens both designed to discover novel mutants impacting on Drosophila metal homeostasis. One screen returned a mutant interacting with ferritin to reduce male fertility (Mehta et al., Biochemical Society Transactions, 2008), contributing to an understanding of the role of iron proteins during spermatogenesis (see also Metzendorf and Lind, BMC Developmental Biology, 2010). A previously suggested specific role of mitochondrial ferritin in testis function (Missirlis et al., Proceedings of the National Academy of Sciences U.S.A., 2006) was investigated and it was shown that a novel mutant also interacts genetically with mitoferrin mutants. A Doctor of Philosophy (PhD) student will continue and develop this line of research and hopefully identify the gene mutated in this stock. From a second screen, which was elaborated upon in the interim report, two separate genetic loci that result in low iron accumulation were identified and studied. One mutation is in a gene with a known function in autophagy. It is speculated that autophagy may be required for ferritin recycling. The second mutation is in a gene involved in glycosylation of secreted proteins. Ferritin is secreted in Drosophila and has the predicted glycosylation site. Both of these findings require further scrutiny and study before they can be published. Overall, the project has progressed our understanding of ferritin regulation (the new information being that different cell types regulate ferritin in different ways). A link between ferritin and behaviour (forced expression of ferritin in glia disrupts normal behaviour in old-aged flies) has been established. An interaction between copper and iron has been rediscovered (copper in the fly diet leads to an iron deficiency; this observation was first made in 1952 by Poulson and Bowen, but had not been revisited since). Finally, zinc accumulation in flies carrying mutations in the pantothenate kinase homologue gene (the human disease gene that leads to iron accumulation in the brain and neurodegeneration) was observed, and follow-up studies are ongoing. The grant has supported the research of Dr Missirlis over a period of 4 years and the data obtained was published (see list of publications) and provided a basis for securing further funding. An application for a Royal Society Grant was successful but efforts to secure more substantial funding have thus far been unsuccessful.

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