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Published on: January 12, 2015
Developmental changes in the expression of ATP7A during a critical period in postnatal neurodevelopment
M J Niciu1, X-M Ma, R El Meskini
1University of Connecticut Health Center, Department of Neuroscience, Academic Research Building (E)-4047, 263 Farmington Avenue, Farmington, CT 06030, USA.
Insights
The ATP7A protein, crucial for copper transport, shows dynamic expression in the developing mouse brain. Its precise regulation highlights the critical window for treating Menkes disease, a neurodegenerative copper disorder.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- ATP7A is a P-type ATPase essential for intracellular copper transport.
- Mutations in ATP7A cause Menkes disease, a fatal copper-deficiency disorder characterized by neurodegeneration.
- Early postnatal copper administration can mitigate Menkes disease symptoms in patients and mouse models.
Purpose of the Study:
- To investigate the neurodevelopmental expression and localization of ATP7A protein in the mouse brain.
- To correlate ATP7A expression patterns with the therapeutic window for Menkes disease.
Main Methods:
- Immunoblot analyses to quantify ATP7A protein levels.
- Immunohistochemistry using an ATP7A-specific antibody for protein localization.
- In situ hybridization studies (previously conducted) to assess ATP7A transcript distribution.
Main Results:
- ATP7A protein expression peaks in the early postnatal period (P4) in the neocortex and cerebellum.
- Highest ATP7A levels are found in choroid plexus/ependymal cells throughout development.
- Expression decreases in most neurons but increases in specific populations like CA2 hippocampal pyramidal and cerebellar Purkinje neurons, and is present in various glial cells and endothelial cells.
Conclusions:
- ATP7A exhibits precise, cell-specific, and developmentally regulated expression in the brain.
- The observed expression patterns, particularly its transient presence in the optic nerve axons, suggest stage-specific functions.
- The tightly controlled neurodevelopmental expression of ATP7A aligns with the limited therapeutic window for Menkes disease treatment.
Abstract:
ATP7A is a P-type ATPase that transports copper from cytosol into the secretory pathway for loading onto cuproproteins or efflux. Mutations in Atp7a cause Menkes disease, a copper-deficiency disorder fatal in the postnatal period due to severe neurodegeneration. Early postnatal copper injections are known to diminish degenerative changes in some human patients and mice bearing mutations in Atp7a. In situ hybridization studies previously demonstrated that ATP7A transcripts are expressed widely in the brain. ATP7A-specific antibody was used to study the neurodevelopmental expression and localization of ATP7A protein in the mouse brain. Based on immunoblot analyses, ATP7A expression is most abundant in the early postnatal period, reaching peak levels at P4 in neocortex and cerebellum. In the developing and adult brain, ATP7A levels are greatest in the choroid plexus/ependymal cells of the lateral and third ventricles. ATP7A expression decreases in most neuronal subpopulations from birth to adulthood. In contrast, ATP7A expression increases in CA2 hippocampal pyramidal and cerebellar Purkinje neurons. ATP7A is expressed in a subset of astrocytes, microglia, oligodendrocytes, tanycytes and endothelial cells. ATP7A is largely localized to the trans-Golgi network, adopting the cell-specific and developmentally-regulated morphology of this organelle. The presence of ATP7A in the axons of postnatal, but not adult, optic nerve suggests stage-specific roles for this enzyme. In sum, the precisely-regulated neurodevelopmental expression of ATP7A correlates well with the limited therapeutic window for effective treatment of Menkes disease.
