The Developmentally Regulated Expression of Menkes Protein ATP7A Suggests a Role in Axon Extension and Synaptogenesis

Meskini, Rajaâ El; Cline, Laura B.; Eipper, Betty A.; Ronnett, Gabriele V.

doi:10.1159/000086713

Cited by 52 publications

(39 citation statements)

References 136 publications

(101 reference statements)

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“…Despite extensive clinical and experimental studies, the pathogenesis of the neuronal disease remains poorly understood, but it does not result from the absence of function of any of the known cuproenzymes expressed within the developing brain (32). Recent studies in a murine model of Menkes disease suggested a role for Atp7a in axon extension and synaptogenesis based on the expression and localization of Atp7a in early development (11). Our findings now reveal a mechanistic role for copper in neuronal physiology that could account for such a role in synaptogenesis and indicate that, in the absence of Atp7a function, the resulting impairment in copper release markedly accentuates NMDA receptor-mediated excitotoxicity (Figs.…”

Section: Discussionsupporting

confidence: 55%

“…In children with Menkes disease, an impairment in copper acquisition in utero due to loss-of-function mutations in the gene encoding a coppertransporting ATPase, Atp7a, results in fatal neurodegeneration associated with intractable seizures, severe hypotonia, and profound developmental delay (8). Pathologic analysis of brain tissue from affected patients reveals neurodegeneration in the cerebral cortex, cerebellum, and hippocampus, consistent with the known sites of the expression of Atp7a within the developing central nervous system (9)(10)(11)(12)(13)(14).…”

mentioning

confidence: 74%

“…Recent studies in the murine olfactory epithelium support a role for Atp7a in axon extension, suggesting mechanisms for the neurodegenerative process in affected patients (11). Previous studies have revealed copper release into the synaptic cleft after neuronal depolarization (15,16).…”

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confidence: 98%

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Role of the Menkes copper-transporting ATPase in NMDA receptor-mediated neuronal toxicity

Schlief

West

Craig

et al. 2006

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

167

129

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Menkes disease, a fatal neurodegenerative disorder resulting in seizures, hypotonia, and failure to thrive, is due to inherited loss-of-function mutations in the gene encoding a copper-transporting ATPase (Atp7a) on the X chromosome. Although affected patients exhibit signs and symptoms of copper deficiency, the mechanisms resulting in neurologic disease remain unknown. We recently discovered that Atp7a is required for the production of an NMDA receptor-dependent releasable copper pool within hippocampal neurons, a finding that suggests a role for copper in activity-dependent modulation of synaptic activity. In support of this hypothesis, we now demonstrate that copper chelation exacerbates NMDA-mediated excitotoxic cell death in primary hippocampal neurons, whereas the addition of copper is specifically protective and results in a significant decrease in cytoplasmic Ca 2؉ levels after NMDA receptor activation. Consistent with the known neuroprotective effect of NMDA receptor nitrosylation, we show here that this protective effect of copper depends on endogenous nitric oxide production in hippocampal neurons, demonstrating in vivo links among neuroprotection, copper metabolism, and nitrosylation. Atp7a is required for these copper-dependent effects: Hippocampal neurons isolated from newborn Mo br mice reveal a marked sensitivity to endogenous glutamate-mediated NMDA receptor-dependent excitotoxicity in vitro, and mild hypoxic͞isch-emic insult to these mice in vivo results in significantly increased caspase 3 activation and neuronal injury. Taken together, these data reveal a unique connection between copper homeostasis and NMDA receptor activity that is of broad relevance to the processes of synaptic plasticity and excitotoxic cell death.excitotoxicity ͉ Menkes disease ͉ brain ͉ newborn

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Section: Discussionsupporting

confidence: 55%

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confidence: 74%

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Role of the Menkes copper-transporting ATPase in NMDA receptor-mediated neuronal toxicity

Schlief

West

Craig

et al. 2006

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

167

129

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“…The transport and cellular metabolism of copper depends on a series of membrane proteins and smaller soluble peptides that comprise a functionally integrated system for maintaining cellular copper homeostasis. Two membrane-bound copper-transporting ATPase enzymes, ATP7A and ATP7B, can catalyse an ATP-dependent transfer of copper to intracellular compartments or expel copper from the cell (Harris, 2000;El Meskini et al, 2005), respectively. A truncated splice variant of ATP7A, termed NML45 (Nuclear Menkes Like) has also been described that encodes a theoretical 11.2-kDa protein with one copper-binding site, and may function as a nuclear copper chaperone (Reddy et al, 2000).…”

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confidence: 99%

“…It is rapidly recycled, returning to the trans-Golgi network once cytoplasmic copper levels are normal (La Fontaine et al, 1999;Lutsenko and Petris, 2003). In neurons ATP7A is developmentally regulated, being initially expressed in cell bodies of developing neurons, with later expression shifting to the extending axons and peaking just prior to synaptogenesis (El Meskini et al, 2005). ATP7A has an important function in neurodevelopment, and is involved in axonal targeting, synaptogenesis and maturation of olfactory sensory neurons (El Meskini et al, 2007).…”

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confidence: 99%

ATP7A is a novel target of retinoic acid receptor β2 in neuroblastoma cells

et al. 2009

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Increased retinoic acid receptor b (RARb 2 ) gene expression is a hallmark of cancer cell responsiveness to retinoid anticancer effects. Moreover, low basal or induced RARb 2 expression is a common feature of many human cancers, suggesting that RARb 2 may act as a tumour suppressor gene in the absence of supplemented retinoid. We have previously shown that low RARb 2 expression is a feature of advanced neuroblastoma. Here, we demonstrate that the ABC domain of the RARb 2 protein alone was sufficient for the growth inhibitory effects of RARb 2 on neuroblastoma cells. ATP7A, the copper efflux pump, is a retinoid-responsive gene, was upregulated by ectopic overexpression of RARb 2 . The ectopic overexpression of the RARb 2 ABC domain was sufficient to induce ATP7A expression, whereas, RARb 2 siRNA blocked the induction of ATP7A expression in retinoid-treated neuroblastoma cells. Forced downregulation of ATP7A reduced copper efflux and increased viability of retinoid-treated neuroblastoma cells. Copper supplementation enhanced cell growth and reduced retinoid-responsiveness, whereas copper chelation reduced the viability and proliferative capacity. Taken together, our data demonstrates ATP7A expression is regulated by retinoic acid receptor b and it has effects on intracellular copper levels, revealing a link between the anticancer action of retinoids and copper metabolism.

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Copper Metabolism,ATP7AandMenkes Disease

Pierson

Lutsenko

Tümer

2015

Encyclopedia of Life Sciences

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ATP7A is an ATP‐driven copper transport protein that plays an essential role in human health. ATP7A is critically involved in dietary copper uptake in the intestine. In addition, ATP7A delivers copper to numerous copper‐dependent enzymes within the secretory pathway and facilitates copper transfer to the brain. Inactivating mutations in ATP7A are associated with severe and often lethal pathologies, such as Menkes disease, occipital horn syndrome, and distal motor neuropathy. Genetic and biochemical studies have demonstrated that disease‐causing mutations disrupt ATP7A in many ways, including disruption of biosynthesis, impairment of stability, inactivation of copper transport activity and disturbance of trafficking behaviour. Cellular studies also indicate that ATP7A is a subject of complex regulation. Despite significant progress in the characterisation of ATP7A's function, cell‐specific regulation of this transporter remains poorly understood. Many aspects of pathologies caused by mutations in ATP7A require further in depth studies. Key Concepts Copper is the third most abundant trace element in the body, after iron and zinc, and it is required for normal function of important copper‐dependent enzymes. Copper deficiency is detrimental to the development and function of many organs especially the central nervous system. Precise regulation of intracellular copper levels is vitally important because, although essential, excess copper has detrimental effects on metabolism. Several transporter molecules and carrier proteins are involved in regulating copper homeostasis. ATP7A is a member of a large family of P‐type ATPases. These ATP‐utilising membrane proteins pump ions across cellular membranes against a concentration gradient. ATP7A is involved in the delivery of copper to cuproenzymes in the secretory pathway and in the export of surplus copper from cells. Genetic defects in ATP7A leads to the X‐linked recessive Menkes disease. Menkes disease is a multi‐systemic lethal disorder, marked by neurodegenerative symptoms and connective tissue manifestations. Most of the clinical features of Menkes disease can be explained by deficiency of various copper‐dependent enzymes. ATP7A mutations vary from single nucleotide changes to microscopically detectable chromosome abnormalities. Ultimate diagnostic proof of Menkes disease is the demonstration of the molecular defect in ATP7A . Menkes disease patients show progressive deterioration of brain function. Administration of copper‐histidine before brain damage may slow the disease progression and result in less severe neurological symptoms.

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The Developmentally Regulated Expression of Menkes Protein ATP7A Suggests a Role in Axon Extension and Synaptogenesis

Cited by 52 publications

References 136 publications

Role of the Menkes copper-transporting ATPase in NMDA receptor-mediated neuronal toxicity

Role of the Menkes copper-transporting ATPase in NMDA receptor-mediated neuronal toxicity

ATP7A is a novel target of retinoic acid receptor β2 in neuroblastoma cells

Copper Metabolism,ATP7AandMenkes Disease

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