Fly model of Menkes and Wilson's diseases used to explore cellular mechanisms

Hartwig C, Méndez GM, Bhattacharjee S, Vrailas-Mortimer AD, Zlatic SA, Freeman AAH, Gokhale A, Concilli M, Werner E, Sapp Savas C, Rudin-Rush S, Palmer L, Shearing N, Margewich L, McArthy J, Taylor S, Roberts B, Lupashin V, Polishchuk RS, Cox DN, Jorquera RA, Faundez V. Golgi-Dependent Copper Homeostasis Sustains Synaptic Development and Mitochondrial Content. J Neurosci. 2020 Nov 17:JN-RM-1284-20. doi: 10.1523/JNEUROSCI.1284-20.2020. PMID: 33208468.

From the abstract:

Rare genetic diseases preponderantly affect the nervous system causing neurodegeneration to neurodevelopmental disorders. This is the case for both Menkes and Wilson disease, arising from mutations in ATP7A and ATP7B, respectively. The ATP7A and ATP7B proteins localize to the Golgi and regulate copper homeostasis. We demonstrate genetic and biochemical interactions between ATP7 paralogs with the Conserved Oligomeric Golgi complex, or COG complex, a Golgi apparatus vesicular tether. Disruption of Drosophila copper homeostasis by ATP7 tissue-specific transgenic expression caused alterations in epidermis, aminergic, sensory, and motor neurons. ... We conclude that the integrity of Golgi-dependent copper homeostasis mechanisms, requiring ATP7 and COG, are necessary to maintain mitochondria functional integrity and localization to synapses. ... These findings suggest communication between the Golgi apparatus and mitochondria through homeostatically controlled cellular copper levels and copper-dependent enzymatic activities in both organelles.

Drosophila experiments help inform study of Menkes disease

Zlatic SA, Vrailas-Mortimer A, Gokhale A, Carey LJ, Scott E, Burch R, McCall MM, Rudin-Rush S, Davis JB, Hartwig C, Werner E, Li L, Petris M, Faundez V. Rare Disease Mechanisms Identified by Genealogical Proteomics of Copper Homeostasis Mutant Pedigrees. Cell Syst. 2018 Jan 30. pii: S2405-4712(18)30008-5. PMID: 29397366.

From the abstract: "Rare neurological diseases shed light onto universal neurobiological processes. However, molecular mechanisms connecting genetic defects to their disease phenotypes are elusive. Here, we obtain mechanistic information by comparing proteomes of cells from individuals with rare disorders with proteomes from their disease-free consanguineous relatives. ... We found connections between copper dyshomeostasis and the UCHL1/PARK5 pathway of Parkinson disease, which we validated with mitochondrial respiration and Drosophila genetics assays. We propose that our genealogical "omics" strategy can be broadly applied to identify mechanisms linking a genomic locus to its phenotypes."

Metal-related diseases studied using Drosophila

Calap-Quintana P, González-Fernández J, Sebastiá-Ortega N, Llorens JV, Moltó MD. Drosophila melanogaster Models of Metal-Related Human Diseases and Metal Toxicity. Int J Mol Sci. 2017 Jul 6;18(7). pii: E1456. PMID: 28684721.

From the abstract: "Iron, copper and zinc are transition metals essential for life ... Organisms have evolved to acquire metals from nutrition and to maintain adequate levels of each metal to avoid damaging effects associated with its deficiency, excess or misplacement. ... many orthologues of the human metal-related genes having been identified and characterized in Drosophila melanogaster. Drosophila has gained appreciation as a useful model for studying human diseases, including those caused by mutations in pathways controlling cellular metal homeostasis. ... This review recapitulates the metabolism of the principal transition metals, namely iron, zinc and copper, in Drosophila and the utility of this organism as an experimental model to explore the role of metal dyshomeostasis in different human diseases. Finally, a summary of the contribution of Drosophila as a model for testing metal toxicity is provided."

Review highlights use of mouse, fly, and other model organisms to study Menkes disease

Lenartowicz M, Krzeptowski W, Lipiński P, Grzmil P, Starzyński R, Pierzchała O, Møller LB. Mottled Mice and Non-Mammalian Models of Menkes Disease. Front Mol Neurosci. 2015 Dec 18;8:72. PMID: 26732058; PMCID: PMC4684000.

From the abstract: "Menkes disease is a multi-systemic copper metabolism disorder caused by mutations in the X-linked ATP7A gene and characterized by progressive neurodegeneration and severe connective tissue defects. .... Mottled mutants closely recapitulate the Menkes phenotype and are invaluable for studying Cu-metabolism. They provide useful models for exploring and testing new forms of therapy in Menkes disease. Recently, non-mammalian models of Menkes disease, Drosophila melanogaster and Danio rerio mutants were used in experiments which would be technically difficult to carry out in mammals."

Fly study relevant to Menkes and Wilson diseases

Hwang JE, de Bruyne M, Warr CG, Burke R. Copper overload and deficiency both adversely affect the central nervous system of Drosophila. Metallomics. 2014 Oct 17. PMID: 25322772.

From the abstract: "The human copper homeostasis disorders Menkes and Wilson disease both have severe neurological symptoms. Menkes is a copper deficiency disorder whereas Wilson disease patients suffer from copper toxicity, indicating that tight control of neuronal copper levels is essential for proper nervous system development and function. Here we examine the consequences of neuronal copper deficiency and excess in the Drosophila melanogaster nervous system, using targeted manipulation of the copper uptake genes Ctr1A and Ctr1B and efflux gene ATP7 in combination with altered dietary copper levels. ... We conclude that both copper overload and excess have detrimental effects on Drosophila neuronal function, reducing overall fly viability as well as impacting on a specific neuropeptide pathway."

Menkes and Wilsons Diseases. Recent report.

Menkes and Wilson diseases are related to copper homeostasis. This study looks at the Drosophila ortholog of the human genes associated with Menkes and Wilson diseases, Drosophila ATP7.

Sellami A, Wegener C, Veenstra JA. Functional significance of the copper transporter ATP7 in peptidergic neurons and endocrine cells in Drosophila melanogaster. FEBS Lett. 2012 Aug 16. PubMed PMID: 22981378.