Copper homeostasis in Drosophila by complex interplay of import, storage and behavioral avoidance

Balamurugan, Krishnaswamy; Egli, Dieter; Hua, Haiqing; Rajaram, Rama; Seisenbacher, Gerhard; Georgiev, Oleg; Schaffner, Walter

doi:10.1038/sj.emboj.7601543

Cited by 68 publications

(82 citation statements)

References 49 publications

(90 reference statements)

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“…MTF-1 is also involved in the cellular defense against other stress conditions, including oxidative stress and hypoxia. While the lack of MTF-1 renders flies sensitive to metals, MTF-1 overexpression confers enhanced protection against heavy metal stress (Balamurugan et al, 2007). Also in our model system, elevated expression of MTF-1 or of one of its major target genes, metallothionein A (MtnA), strongly ameliorated Ab toxicity ( Figure 5C, D).…”

Section: Figurementioning

confidence: 74%

Toxicity of Alzheimer's disease-associated Aβ peptide is ameliorated in a Drosophila model by tight control of zinc and copper availability

Hua

Munter

Harmeier

et al. 2011

Biological Chemistry

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Amyloid plaques consisting of aggregated Ab peptide are a hallmark of Alzheimer's disease. Among the different forms of Ab, the one of 42aa length (Ab42) is most aggregationprone and also the most neurotoxic. We find that eye-specific expression of human Ab42 in Drosophila results in a degeneration of eye structures that progresses with age. Dietary supplements of zinc or copper ions exacerbate eye damage. Positive effects are seen with zinc/copper chelators, or with elevated expression of MTF-1, a transcription factor with a key role in metal homeostasis and detoxification, or with human or fly transgenes encoding metallothioneins, metal scavenger proteins. These results show that a tight control of zinc and copper availability can minimize cellular damage associated with Ab42 expression.

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Section: Figurementioning

confidence: 74%

Toxicity of Alzheimer's disease-associated Aβ peptide is ameliorated in a Drosophila model by tight control of zinc and copper availability

Hua

Munter

Harmeier

et al. 2011

Biological Chemistry

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“…1D). Notably, forcible overexpression of Ctr1B by itself results in early lethality when driven by Elav-Gal4 and rough eye when driven by GMRGal4 (19), precluding this aspect of analysis in the HD model.…”

Section: Identification Of Copper Transporter Ctr1b As a Geneticallymentioning

confidence: 99%

“…Metallothioneins (Mtn), as metal detoxifiers in the cells (24), are transcriptionally induced by copper and are considered sensitive indicators of intracellular copper levels (19,24). Ctr1B-RNAi and DmATP7-OE flies showed a significant reduction of both MtnA and MtnB, whereas DmATP7-RNAi flies displayed increased levels of MtnA expression ( Fig.…”

Section: Identification Of Copper Transporter Ctr1b As a Geneticallymentioning

confidence: 99%

“…Because Ctr1B has been shown to be a copper transporter in the fly (19,23), we reasoned that other copper transporters might also interact with the HD model. In addition to Ctr1B, the Drosophila genome encodes three other copper transporters including copper transporter1A (Ctr1A), Copper transporter 1C (Ctr1C), and DmATP7.…”

Section: Identification Of Copper Transporter Ctr1b As a Geneticallymentioning

confidence: 99%

“…In Drosophila melanogaster, copper uptake and efflux are mediated by Copper transporter 1 (Ctr1A/B/C) and Drosophila melanogaster ATP7 (DmATP7) (19), respectively. Ctr1A/B/C are the three Drosophila homologs of human Ctr1, which localizes to the cell membrane and plays major roles in cellular copper uptake (20).…”

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confidence: 99%

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Huntington disease arises from a combinatory toxicity of polyglutamine and copper binding

Xiao

Fan

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

128

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Huntington disease (HD) is a progressive neurodegenerative disorder caused by dominant polyglutamine (polyQ) expansion within the N terminus of huntingtin (Htt) protein. Abnormal metal accumulation in the striatum of HD patients has been reported for many years, but a causative relationship has not yet been established. Furthermore, if metal is indeed involved in HD, the underlying mechanism needs to be explored. Here using a Drosophila model of HD, wherein Htt exon1 with expanded polyQ (Htt exon1-polyQ) is introduced, we show that altered expression of genes involved in copper metabolism significantly modulates the HD progression. Intervention of dietary copper levels also modifies HD phenotypes in the fly. Copper reduction to a large extent decreases the level of oligomerized and aggregated Htt. Strikingly, substitution of two potential copper-binding residues of Htt, Met8 and His82, completely dissociates the copper-intensifying toxicity of Htt exon1-polyQ. Our results therefore indicate HD entails two levels of toxicity: the copper-facilitated protein aggregation as conferred by a direct copper binding in the exon1 and the copper-independent polyQ toxicity. The existence of these two parallel pathways converging into Htt toxicity also suggests that an ideal HD therapy would be a multipronged approach that takes both these actions into consideration.

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Comparative Genomics Analysis of the Metallomes

Gladyshev

Zhang

2012

Metal Ions in Life Sciences

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Biological trace metals are needed in small quantities, but used by all living organisms. They are employed in key cellular functions in a variety of biological processes, resulting in the various degree of dependence of organisms on metals. Most effort in the field has been placed on experimental studies of metal utilization pathways and metal-dependent proteins. On the other hand, systemic level analyses of metalloproteomes (or metallomes) have been limited for most metals. In this chapter, we focus on the recent advances in comparative genomics, which provides many insights into evolution and function of metal utilization. These studies suggested that iron and zinc are widely used in biology (presumably by all organisms), whereas some other metals such as copper, molybdenum, nickel, and cobalt, show scattered occurrence in various groups of organisms. For these metals, most user proteins are well characterized and their dependence on a specific element is evolutionarily conserved. We also discuss evolutionary dynamics of the dependence of user proteins on different metals. Overall, comparative genomics analysis of metallomes provides a foundation for the systemic level understanding of metal utilization as well as for investigating the general features, functions, and evolutionary dynamics of metal use in the three domains of life.

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Copper homeostasis in Drosophila by complex interplay of import, storage and behavioral avoidance

Cited by 68 publications

References 49 publications

Toxicity of Alzheimer's disease-associated Aβ peptide is ameliorated in a Drosophila model by tight control of zinc and copper availability

Toxicity of Alzheimer's disease-associated Aβ peptide is ameliorated in a Drosophila model by tight control of zinc and copper availability

Huntington disease arises from a combinatory toxicity of polyglutamine and copper binding

Comparative Genomics Analysis of the Metallomes

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