Peptidylgycine α‐amidating monooxygenase and copper: A gene–nutrient interaction critical to nervous system function

Bousquet-Moore, Danielle; Mains, Richard E.; Eipper, Betty A.

doi:10.1002/jnr.22404

Cited by 64 publications

(54 citation statements)

References 129 publications

(170 reference statements)

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“…The close overlap between Atp7a and PAM expression patterns builds on previous experiments demonstrating the bi‐directional relationship between PAM and Cu and indicates that these proteins may be involved in a common regulatory pathway for Cu homeostasis (Bousquet‐Moore et al . ). In this way, disruption in PAM expression by haploinsufficiency could lead to altered Cu homeostasis in affected brain regions, namely the amygdala.…”

Section: Discussionmentioning

confidence: 97%

Peptidylglycine α‐amidating monooxygenase heterozygosity alters brain copper handling with region specificity

Gaier

Miller

Ralle

et al. 2013

Journal of Neurochemistry

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Copper (Cu), an essential trace element present throughout the mammalian nervous system, is crucial for normal synaptic function. Neuronal handling of Cu is poorly understood. We studied the localization and expression of Atp7a, the major intracellular Cu transporter in the brain, and its relation to peptidylglycine α-amidating monooxygenase (PAM), an essential cuproenzyme and regulator of Cu homeostasis in neuroendocrine cells. Based on biochemical fractionation and immunostaining of dissociated neurons, Atp7a was enriched in postsynaptic vesicular fractions. Cu followed a similar pattern, with ~20% of total Cu in synaptosomes. A mouse model heterozygous for the Pam gene (PAM+/−) is selectively Cu deficient in the amygdala. As in cortex and hippocampus, Atp7a and PAM expression overlap in the amygdala, with highest expression in interneurons. Messenger RNA levels of Atox-1 and Atp7a, which deliver Cu to the secretory pathway, were reduced in the amygdala but not the hippocampus in PAM+/− mice, along with GABAB receptor mRNA levels. Consistent with Cu deficiency, dopamine β-monooxygenase function was impaired as evidenced by elevated dopamine metabolites in the amygdala, but not the hippocampus, of PAM+/− mice. These alterations in Cu delivery to the secretory pathway in the PAM+/− amygdala may contribute to the physiological and behavioral deficits observed.

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Section: Discussionmentioning

confidence: 97%

Peptidylglycine α‐amidating monooxygenase heterozygosity alters brain copper handling with region specificity

Gaier

Miller

Ralle

et al. 2013

Journal of Neurochemistry

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“…The mechanisms by which copper deficiency cause these defects remain unclear. One copper-requiring enzyme is the peptide-processing enzyme peptidyl alpha-amidating monoxygenase (PAM)(Bousquet-Moore et al, 2010), which is highly enriched in sciatic nerve relative to the DRG despite the absence of known peptide precursors that generate amidated peptides (Fig 5). PAM has been reported previously in Schwann cells (Rhodes et al, 1990), although it remains unclear what accounts for its extremely high level of relative expression, or if it could also be expressed in fibroblasts, adipocytes, or vascular endothelium within the nerve sheath.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analyses of genes and tissues in inherited sensory neuropathies

Sapio

Goswami

Gross

et al. 2016

Experimental Neurology

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Inherited sensory neuropathies are caused by mutations in genes affecting either primary afferent neurons, or the Schwann cells that myelinate them. Using RNA-Seq, we analyzed the transcriptome of human and rat DRG and peripheral nerve, which contain sensory neurons and Schwann cells, respectively. We subdivide inherited sensory neuropathies based on expression of the mutated gene in these tissues, as well as in mouse TRPV1 lineage DRG nociceptive neurons, and across 32 human tissues from the Human Protein Atlas. We propose that this comprehensive approach to neuropathy gene expression leads to better understanding of the involved cell types in patients with these disorders. We also characterize the genetic “fingerprint” of both tissues, and present the highly tissue-specific genes in DRG and sciatic nerve that may aid in the development of gene panels to improve diagnostics for genetic neuropathies, and may represent specific drug targets for diseases of these tissues.

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“…This process is crucial in the activation of hormones since over half of all peptide hormones must be α-amidated to be bioactive. 565 PAM has been isolated from a number of mammalian sources including bovine 563 , mouse 566 and rat 567 and is found in Drosophila 568 . Deletion of the PAM gene in Drosophila results in the absence of amidated peptides and leads to late embryo or early larva death.…”

Section: Copper Active Sites That Activate Dioxygenmentioning

confidence: 99%