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Cp/Heph mutant mice have iron‐induced neurodegeneration diminished by deferiprone
Author(s) -
Zhao Liangliang,
Hadziahmetovic Majda,
Wang Chenguang,
Xu Xueying,
Song Ying,
Jinnah H.A.,
Wodzinska Jolanta,
Iacovelli Jared,
Wolkow Natalie,
Krajacic Predrag,
Weissberger Alyssa Cwanger,
Connelly John,
Spino Michael,
Lee Michael K.,
Connor James,
Giasson Benoit,
Leah Harris Z.,
Dunaief Joshua L.
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13292
Subject(s) - ceruloplasmin , ferroportin , deferiprone , neurodegeneration , dmt1 , mutant , chemistry , ataxia , microbiology and biotechnology , biochemistry , biology , neuroscience , medicine , iron homeostasis , metabolism , deferoxamine , transporter , disease , gene
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.