Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022716 (Menkes)
 1,057 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Copper is an essential transition metal with a critical role in the CNS. This requirement is underscored by Menkes disease, a fatal neurodegenerative disorder of childhood resulting from the absence or dysfunction of a copper-transporting P-type ATPase. To elucidate the cell biological mechanisms of copper homeostasis in the CNS, a polyclonal antisera against Menkes ATPase was used in immunoblot and immunohistochemical studies, demonstrating abundant expression of this copper transporter in hippocampal neurons. Consistent with this observation, immunofluorescent analysis revealed Menkes ATPase in the late Golgi of hippocampal neurons in primary culture. Glutamate receptor activation was found to result in the rapid and reversible trafficking of Menkes ATPase to neuronal processes, independent of the intracellular copper concentration and specific for activation of the NMDA- but not AMPA/kainate-type glutamate receptors. Metabolic studies revealed that trafficking of Menkes ATPase after NMDA receptor activation is associated with rapid release of copper from hippocampal neurons. Menkes ATPase is directly required for this copper efflux, because similar studies in hippocampal neurons derived from mice lacking a functional Menkes ATPase demonstrated no copper release. Together, these data reveal a critical role for Menkes ATPase in the availability of an NMDA receptor-dependent, releasable pool of copper in hippocampal neurons and demonstrate a unique mechanism linking copper homeostasis and neuronal activation within the CNS.
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PMID:NMDA receptor activation mediates copper homeostasis in hippocampal neurons. 1563 87

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 hypoxic/ischemic 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.
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PMID:Role of the Menkes copper-transporting ATPase in NMDA receptor-mediated neuronal toxicity. 1700 21

Menkes disease is a fatal neurodegenerative disorder arising from a systemic copper deficiency caused by loss-of-function mutations in a ubiquitously expressed copper transporter, ATP7A. Although this disorder reveals an essential role for copper in the developing human nervous system, the role of ATP7A in the pathogenesis of signs and symptoms in affected patients, including severe mental retardation, ataxia, and excitotoxic seizures, remains unknown. To directly examine the role of ATP7A within the central nervous system, we generated Atp7a(Nes) mice, in which the Atp7a gene was specifically deleted within neural and glial cell precursors without impairing systemic copper homeostasis, and compared these mice with the mottled brindle (mo-br) mutant, a murine model of Menkes disease in which Atp7a is defective in all cells. Whereas mo-br mice displayed neurodegeneration, demyelination, and 100% mortality prior to weaning, the Atp7a(Nes) mice showed none of these phenotypes, exhibiting only mild sensorimotor deficits, increased anxiety, and susceptibility to NMDA-induced seizure. Our results indicate that the pathophysiology of severe neurological signs and symptoms in Menkes disease is the result of copper deficiency within the central nervous system secondary to impaired systemic copper homeostasis and does not arise from an intrinsic lack of ATP7A within the developing brain. Furthermore, the sensorimotor deficits, hypophagia, anxiety, and sensitivity to NMDA-induced seizure in the Atp7a(Nes) mice reveal unique autonomous requirements for ATP7A in the nervous system. Taken together, these data reveal essential roles for copper acquisition in the central nervous system in early development and suggest novel therapeutic approaches in affected patients.
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PMID:Autonomous requirements of the Menkes disease protein in the nervous system. 2646 9