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Author Notes:

Corresponding author. 305 Stellar Chance Labs, 422 Curie Blvd., Philadelphia, PA 19104; Email: jdunaief@upenn.edu, 215-898-5235.

The Dunaief lab receives research funding from ApoPharma, Inc., and JLD is co-inventor on a patent pending for use of deferiprone for age-related macular degeneration. Michael Spino, John Connelly, and Jolanta Wodzinska are employees of ApoPharma.

All experiments were conducted in compliance with the ARRIVE guidelines.

Subjects:

Research Funding:

This work was funded by The Paul and Evanina Bell Mackall Foundation Trust, The F.M. Kirby Foundation, National Institutes of Health, (Grant/Award Number: ‘NIH EY015240’).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Neurosciences
  • Neurosciences & Neurology
  • ceruloplasmin/Hephaestin
  • deferiprone
  • glia
  • iron
  • neurodegeneration
  • oxidative stress
  • CENTRAL-NERVOUS-SYSTEM
  • BLOOD-BRAIN-BARRIER
  • LEWY BODY DISEASE
  • PARKINSONS-DISEASE
  • OXIDATIVE STRESS
  • CELL-DEATH
  • MICROGLIAL ACTIVATION
  • MACULAR DEGENERATION
  • CERULOPLASMIN GENE
  • FRIEDREICH ATAXIA

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

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Journal Title:

Journal of Neurochemistry

Volume:

Volume 135, Number 5

Publisher:

, Pages 958-974

Type of Work:

Article | Post-print: After Peer Review

Abstract:

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.

Copyright information:

© 2015 International Society for Neurochemistry.

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