title: A Drosophila model of Menkes disease reveals a role for DmATP7 in copper absorption and neurodevelopment.
abstract: Human Menkes disease is a lethal neurodegenerative disorder of copper metabolism that is caused by mutations in the ATP7A copper-transporting gene. In the present study, we attempted to construct a Drosophila model of Menkes disease by RNA interference (RNAi)-induced silencing of DmATP7, the Drosophila orthologue of mammalian ATP7A, in the digestive tract. Here, we show that a lowered level of DmATP7 mRNA in the digestive tract results in a reduced copper content in the head and the rest of the body of surviving adults, presumably owing to copper entrapment in the gut. Similar to Menkes patients, a majority of flies exhibit an impaired neurological development during metamorphosis and die before eclosion. In addition, we show that survival to the adult stage is highly dependent on the copper content of the food and that overexpression of the copper homeostasis gene, metal-responsive transcription factor-1 (MTF-1), enhances survival to the adulthood stage. Taken together, these results highlight the role of DmATP7-mediated copper uptake in the neurodevelopment of Drosophila melanogaster and provide a framework for the analysis of potential gene interactions influencing Menkes disease.
authors.affiliation: Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada.
authors.forename: Sepehr
authors.initials: S
authors.lastname: Bahadorani
authors.forename: Peyman
authors.initials: P
authors.lastname: Bahadorani
authors.forename: Edyta
authors.initials: E
authors.lastname: Marcon
authors.forename: David W
authors.initials: DW
authors.lastname: Walker
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Hilliker
mesh_terms: D000042:Absorption / Q000187:drug effects; D000375:Aging / Q000187:drug effects / Q000473:pathology; D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism*; D003300:Copper / Q000378:metabolism* / Q000494:pharmacology; D000073840:Copper-Transporting ATPases; D004268:DNA-Binding Proteins / Q000378:metabolism; D019587:Dietary Supplements; D004064:Digestive System / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D017344:Genes, Insect / Q000235:genetics; D007814:Larva / Q000187:drug effects / Q000378:metabolism; D007706:Menkes Kinky Hair Syndrome; D009420:Nervous System / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D011679:Pupa / Q000187:drug effects / Q000378:metabolism; D034622:RNA Interference / Q000187:drug effects; D013489:Suppression, Genetic / Q000187:drug effects; D016019:Survival Analysis; D014157:Transcription Factors / Q000378:metabolism; D000097809:Transcription Factor MTF-1
chemical_list: D027682:Cation Transport Proteins; D003300:Copper; D000073840:Copper-Transporting ATPases; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D000097809:Transcription Factor MTF-1; C497836:ATP7 protein, Drosophila