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

被引：33

作者：

Zhao, Liangliang ^{[1
,2
]}

Hadziahmetovic, Majda ^{[1
,3
]}

Wang, Chenguang ^{[1
,2
]}

Xu, Xueying ^{[4
]}

Song, Ying ^{[1
]}

Jinnah, H. A. ^{[5
]}

Wodzinska, Jolanta ^{[6
]}

Iacovelli, Jared ^{[1
]}

Wolkow, Natalie ^{[1
]}

Krajacic, Predrag ^{[1
]}

Weissberger, Alyssa Cwanger ^{[1
]}

Connelly, John ^{[6
]}

Spino, Michael ^{[6
,7
]}

Lee, Michael K. ^{[8
]}

Connor, James ^{[9
]}

Giasson, Benoit ^{[10
]}

Harris, Z. Leah ^{[11
]}

Dunaief, Joshua L. ^{[1
]}

机构：

[1] Univ Penn, Scheie Eye Inst, FM Kirby Ctr Mol Ophthalmol, Philadelphia, PA 19104 USA

[2] Jilin Univ, Hosp 2, Dept Ophthalmol, Changchun, Jilin, Peoples R China

[3] Drexel Univ, Coll Med, Dept Ophthalmol, Philadelphia, PA 19104 USA

[4] Sinai Hosp, Dept Med, Baltimore, MD 21215 USA

[5] Emory Univ, Sch Med, Dept Neurol Human Genet & Pediat, Atlanta, GA USA

[6] ApoPharma Inc, Toronto, CA USA

[7] Univ Toronto, Leslie Dan Fac Pharm, Toronto, ON M5S 3M2, Canada

[8] Univ Minnesota, Dept Neurosci, Minneapolis, MN USA

[9] Penn State Milton S Hershey Med Ctr, Dept Neurosurg, Hershey, PA USA

[10] Univ Florida, Coll Med, Dept Neurosci, Gainesville, FL 32610 USA

[11] Northwestern Univ, Ann & Robert H Lurie Childrens Hosp Chicago, Dept Pediat, Chicago, IL 60611 USA

来源：

JOURNAL OF NEUROCHEMISTRY | 2015年 / 135卷 / 05期

基金：

美国国家卫生研究院;

关键词：

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;

D O I：

10.1111/jnc.13292

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：958 / 974

页数：17

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