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Cp/Heph mutant mice have iron-induced neurodegeneration diminished by deferiprone.

Publication ,  Journal Article
Zhao, L; Hadziahmetovic, M; Wang, C; Xu, X; Song, Y; Jinnah, HA; Wodzinska, J; Iacovelli, J; Wolkow, N; Krajacic, P; Weissberger, AC; Spino, M ...
Published in: J Neurochem
December 2015

Brain iron accumulates in several neurodegenerative diseases and can cause oxidative damage, but mechanisms of brain iron homeostasis are incompletely understood. Patients with mutations in the cellular iron-exporting ferroxidase ceruloplasmin (Cp) have brain iron accumulation causing neurodegeneration. Here, we assessed the brains of mice with combined mutation of Cp and its homolog hephaestin. Compared to single mutants, brain iron accumulation was accelerated in double mutants in the cerebellum, substantia nigra, and hippocampus. Iron accumulated within glia, while neurons were iron deficient. There was loss of both neurons and glia. Mice developed ataxia and tremor, and most died by 9 months. Treatment with the oral iron chelator deferiprone diminished brain iron levels, protected against neuron loss, and extended lifespan. Ferroxidases play important, partially overlapping roles in brain iron homeostasis by facilitating iron export from glia, making iron available to neurons. Above: Iron (Fe) normally moves from capillaries to glia to neurons. It is exported from the glia by ferroportin (Fpn) with ferroxidases ceruloplasmin (Cp) and/or Hephaestin (Heph). Below: In mice with mutation of Cp and Heph, iron accumulates in glia, while neurons have low iron levels. Both neurons and glia degenerate and mice become ataxic unless given an iron chelator.

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Published In

J Neurochem

DOI

EISSN

1471-4159

Publication Date

December 2015

Volume

135

Issue

5

Start / End Page

958 / 974

Location

England

Related Subject Headings

  • Tyrosine 3-Monooxygenase
  • Pyridones
  • Oxidative Stress
  • Neurons
  • Neurology & Neurosurgery
  • Neuroglia
  • Neurodegenerative Diseases
  • Nerve Tissue Proteins
  • Myelin Basic Protein
  • Mutation
 

Citation

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Zhao, L., Hadziahmetovic, M., Wang, C., Xu, X., Song, Y., Jinnah, H. A., … Dunaief, J. L. (2015). Cp/Heph mutant mice have iron-induced neurodegeneration diminished by deferiprone. J Neurochem, 135(5), 958–974. https://doi.org/10.1111/jnc.13292
Zhao, Liangliang, Majda Hadziahmetovic, Chenguang Wang, Xueying Xu, Ying Song, H. A. Jinnah, Jolanta Wodzinska, et al. “Cp/Heph mutant mice have iron-induced neurodegeneration diminished by deferiprone.J Neurochem 135, no. 5 (December 2015): 958–74. https://doi.org/10.1111/jnc.13292.
Zhao L, Hadziahmetovic M, Wang C, Xu X, Song Y, Jinnah HA, et al. Cp/Heph mutant mice have iron-induced neurodegeneration diminished by deferiprone. J Neurochem. 2015 Dec;135(5):958–74.
Zhao, Liangliang, et al. “Cp/Heph mutant mice have iron-induced neurodegeneration diminished by deferiprone.J Neurochem, vol. 135, no. 5, Dec. 2015, pp. 958–74. Pubmed, doi:10.1111/jnc.13292.
Zhao L, Hadziahmetovic M, Wang C, Xu X, Song Y, Jinnah HA, Wodzinska J, Iacovelli J, Wolkow N, Krajacic P, Weissberger AC, Connelly J, Spino M, Lee MK, Connor J, Giasson B, Harris ZL, Dunaief JL. Cp/Heph mutant mice have iron-induced neurodegeneration diminished by deferiprone. J Neurochem. 2015 Dec;135(5):958–974.
Journal cover image

Published In

J Neurochem

DOI

EISSN

1471-4159

Publication Date

December 2015

Volume

135

Issue

5

Start / End Page

958 / 974

Location

England

Related Subject Headings

  • Tyrosine 3-Monooxygenase
  • Pyridones
  • Oxidative Stress
  • Neurons
  • Neurology & Neurosurgery
  • Neuroglia
  • Neurodegenerative Diseases
  • Nerve Tissue Proteins
  • Myelin Basic Protein
  • Mutation