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Cp/Heph mutant mice have iron-induced neurodegeneration diminished by deferiprone
Journal article   Open access   Peer reviewed

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

Liangliang Zhao, Majda Hadziahmetovic, Chenguang Wang, Xueying Xu, Ying Song, H A Jinnah, Jolanta Wodzinska, Jared Iacovelli, Natalie Wolkow, Predrag Krajacic, …
Journal of neurochemistry, v 135(5), pp 958-974
Dec 2015
DOI: https://doi.org/10.1111/jnc.13292
PMID: 26303407
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://europepmc.org/articles/pmc4943332View
Accepted (AM)Open Access (License Unspecified),  Open
url
https://doi.org/10.1111/jnc.13292View
Published, Version of Record (VoR) Open

Abstract

Animals Brain - metabolism Brain - pathology Ceruloplasmin - genetics Ceruloplasmin - metabolism Disease Models, Animal Iron - metabolism Iron Chelating Agents - therapeutic use Membrane Proteins - genetics Membrane Proteins - metabolism Mice Mice, Transgenic Motor Activity - drug effects Motor Activity - genetics Muscle Strength - drug effects Muscle Strength - genetics Mutation - genetics Myelin Basic Protein - metabolism Nerve Tissue Proteins - metabolism Neurodegenerative Diseases - drug therapy Neurodegenerative Diseases - genetics Neurodegenerative Diseases - metabolism Neuroglia - drug effects Neuroglia - metabolism Neurons - drug effects Neurons - metabolism Oxidative Stress - drug effects Oxidative Stress - genetics Pyridones - therapeutic use Tyrosine 3-Monooxygenase - metabolism
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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31 citations in Web of Science
32 citations in Scopus

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Collaboration types
Domestic collaboration
International collaboration
Web of Science research areas
Biochemistry & Molecular Biology
Neurosciences
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