Localization of Menkes gene expression in the mouse brain; its association with neurological manifestations in Menkes model mice

Iwase, Toshio; Nishimura, Masahiko; Sugimura, Haruhiko; Igarashi, Hisaki; Ozawa, Fukujiro; Shinmura, Kazuya; Tanaka, Masamitsu; Kino, Isamu

doi:10.1007/s004010050455

Cited by 44 publications

(36 citation statements)

References 21 publications

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“…Importantly, these findings demonstrate a direct link between ionotropic receptor activity in hippocampal neurons, a process critical to neuronal function, and copper homeostasis in these same cells. Our observation that Menkes ATPase is expressed in several brain regions is consistent with previous studies of Menkes mRNA expression in the mouse brain (Iwase et al, 1996;Murata et al, 1997) and suggests that similar mechanisms linking neuronal activation and copper homeostasis may exist in other neuronal cell types in the CNS.…”

Section: Discussionsupporting

confidence: 91%

NMDA Receptor Activation Mediates Copper Homeostasis in Hippocampal Neurons

Schlief

Craig²,

Gitlin³

2005

J. Neurosci.

273

229

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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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Section: Discussionsupporting

confidence: 91%

NMDA Receptor Activation Mediates Copper Homeostasis in Hippocampal Neurons

Schlief

Craig²,

Gitlin³

2005

J. Neurosci.

273

229

View full text Add to dashboard Cite

show abstract

“…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: 67%

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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“…Current data suggest that MNKP controls the overall copper supply to the brain through its localization in choroid plexus (12) and also has a biosynthetic role in pituitary gland where it mediates copper delivery to peptidyl-glycine ␣-amidating monooxygenase (13). What physiological functions the copper-transporting ATPases have in other brain regions and what the relationship is between MNKP and WNDP in either adult or developing brain remain unknown.…”

mentioning

confidence: 99%