Journal article
Altered ATP7A expression and other compensatory responses in a murine model of Menkes disease
Neurobiology of disease, Vol.27(3), pp.278-291
2007
DOI: 10.1016/j.nbd.2007.05.004
PMCID: PMC2040029
PMID: 17588765
Abstract
Mutations in the copper-transporter ATP7A lead to severe neurodegeneration in the mottled brindled hemizygous male (Mo
Br/y) mouse and human patients with Menkes disease. Our earlier studies demonstrated cell-type- and -stage-specific changes in ATP7A protein expression during postnatal neurodevelopment. Here we examined copper and cuproenzyme levels in Mo
Br/y mice to search for compensatory responses. While all Mo
Br/y neocortical subcellular fractions had decreased copper levels, the greatest decrease (8-fold) was observed in cytosol. Immunostaining for ATP7A revealed decreased levels in Mo
Br/y hippocampal pyramidal and cerebellar Purkinje neurons. In contrast, an upregulation of ATP7A protein occurred in Mo
Br/y endothelial cells, perhaps to compensate for a lack of copper in the neuropil. Mo
Br/y astrocytes and microglia increased their physical association with the blood–brain barrier. No alterations in ATP7A levels were observed in ependymal cells, arguing for specificity in the alteration observed at the blood–brain barrier. The decreased expression of ATP7A protein in Mo
Br/y Purkinje cells was associated with impaired synaptogenesis and dramatic cytoskeletal dysfunction. Immunoblotting failed to reveal any compensatory increase in levels of ATP7B. While total levels of several cuproenzymes (peptide-amidating monooxygenase, SOD1, and SOD3) were unaltered in the Mo
Br/y brain, levels of amidated cholecystokinin (CCK8) and amidated pituitary adenylate cyclase-activating polypeptide (PACAP38) were reduced in a tissue-specific fashion. The compensatory changes observed in the neurovascular unit provide insight into the success of copper injections within a defined neurodevelopmental period.
Details
- Title: Subtitle
- Altered ATP7A expression and other compensatory responses in a murine model of Menkes disease
- Creators
- Mark J Niciu - University of Connecticut Health Center, Department of Neuroscience, Academic Research Building (E)-4047 1, 263 Farmington Avenue, Farmington, CT 06030-3401, USAXin-Ming Ma - University of Connecticut Health Center, Department of Neuroscience, Academic Research Building (E)-4047 1, 263 Farmington Avenue, Farmington, CT 06030-3401, USARajaâ El Meskini - University of Connecticut Health Center, Department of Neuroscience, Academic Research Building (E)-4047 1, 263 Farmington Avenue, Farmington, CT 06030-3401, USAJoel S Pachter - University of Connecticut Health Center, Blood–Brain Barrier Laboratory, Department of Pharmacology, 263 Farmington Avenue, Farmington, CT 06030, USARichard E Mains - University of Connecticut Health Center, Department of Neuroscience, Academic Research Building (E)-4047 1, 263 Farmington Avenue, Farmington, CT 06030-3401, USABetty A Eipper - University of Connecticut Health Center, Department of Neuroscience, Academic Research Building (E)-4047 1, 263 Farmington Avenue, Farmington, CT 06030-3401, USA
- Resource Type
- Journal article
- Publication Details
- Neurobiology of disease, Vol.27(3), pp.278-291
- DOI
- 10.1016/j.nbd.2007.05.004
- PMID
- 17588765
- PMCID
- PMC2040029
- NLM abbreviation
- Neurobiol Dis
- ISSN
- 0969-9961
- eISSN
- 1095-953X
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: DK-32949, GM-08607
- Language
- English
- Date published
- 2007
- Academic Unit
- Psychiatry; Iowa Neuroscience Institute
- Record Identifier
- 9984003964902771
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