ATP7A (Menkes protein) functions in axonal targeting and synaptogenesis

Rajaâ El Meskini, Kelli L. Crabtree, Laura B. Cline, Richard E. Mains, Betty A. Eipper, Gabriele V. Ronnett

Research output: Contribution to journalArticlepeer-review

Abstract

Menkes disease (MD) is a neurodegenerative disorder caused by mutations in the copper transporter, ATP7A, a P-type ATPase. We previously used the olfactory system to demonstrate that ATP7A expression is developmentally, not constitutive, regulated, peaking during synaptogenesis when it is highly expressed in extending axons in a copper-independent manner. Although not known to be associated with axonal functions, we explored the possibility that the inability of mutant ATP7A to support axon outgrowth contributes to the neurodegeneration seen in MD. In vivo analysis of the olfactory system in mottled brindled (Atp7aMobr) mice, a rodent model for MD, demonstrates that ATP7A deficiency affects olfactory sensory neuron (OSN) maturation. Disrupted OSN axonal projections and mitral/tufted cell dendritic growth lead to altered synapse integrity and glomerular disorganization in the olfactory bulbs of Atp7aMobr mice. Our data indicate that the neuronal abnormalities observed in MD are a result of specific age-dependent developmental defects. This study demonstrates a role for ATP7A and/or copper in axon outgrowth and synaptogenesis, and will further help identify the cause of the neuropathology that characterizes MD.

Original languageEnglish (US)
Pages (from-to)409-421
Number of pages13
JournalMolecular and Cellular Neuroscience
Volume34
Issue number3
DOIs
StatePublished - Mar 2007

Keywords

  • ATP7A
  • Axonal outgrowth
  • Menkes disease
  • Neurodevelopment
  • Olfactory sensory neurons
  • Olfactory system
  • Synapse

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Developmental Neuroscience

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