Neonatal iron supplementation potentiates oxidative stress, energetic dysfunction and neurodegeneration in the R6/2 mouse model of Huntington's disease

被引:31
作者
Berggren, Kiersten L. [1 ]
Chen, Jianfang [1 ,2 ]
Fox, Julia [1 ]
Miller, Jonathan [1 ]
Dodds, Lindsay [1 ]
Dugas, Bryan [1 ]
Vargas, Liset [1 ]
Lothian, Amber [3 ]
McAllum, Erin [3 ]
Volitakis, Irene [3 ]
Roberts, Blaine [3 ]
Bush, Ashley I. [3 ]
Fox, Jonathan H. [1 ,2 ]
机构
[1] Univ Wyoming, Dept Vet Sci, Laramie, WY 82070 USA
[2] Univ Wyoming, Neurosci Grad Program, Laramie, WY 82070 USA
[3] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic 3010, Australia
关键词
Huntington's; Iron; Neurodegeneration; Oxidative stress; Stereology; Gene environment interaction; MUTANT HUNTINGTIN; TRANSGENIC MOUSE; IN-VIVO; TRINUCLEOTIDE REPEAT; CAG REPEAT; BRAIN; MICE; PROGRESSION; HOMEOSTASIS; IMPAIRMENT;
D O I
10.1016/j.redox.2015.02.002
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion that encodes a polyglutamine tract in huntingtin (htt) protein. Dysregulation of brain iron homeostasis, oxidative stress and neurodegeneration are consistent features of the HD phenotype. Therefore, environmental factors that exacerbate oxidative stress and iron dysregulation may potentiate HD. lion supplementation in the human population is common during infant and adult-life stages. In this study, iron supplementation in neonatal HD mice resulted in deterioration of spontaneous motor running activity, elevated levels of brain lactate and oxidized glutathione consistent with increased energetic dysfunction and oxidative stress, and increased striatal and motor cortical neuronal atrophy, collectively demonstrating potentiation of the disease phenotype. Oxidative stress, energetic, and anatomic markers of degeneration were not affected in wild-type littermate iron-supplemented mice. Further, there was no effect of elevated iron intake on disease outcomes in adult HD mice. We have demonstrated an interaction between the mutant huntingtin gene and iron supplementation in neonatal HD mice. Findings indicate that elevated neonatal iron intake potentiates mouse HD and promotes oxidative stress and energetic dysfunction in brain. Neonatal-infant dietary iron intake level may be an environmental modifier of human HD. (C) 2015 The Authors. Published by Elsevier B.V.
引用
收藏
页码:363 / 374
页数:12
相关论文
共 48 条
[1]
Genetic modifiers of Huntington's disease: beyond CAG [J].
Arning, Larissa ;
Epplen, Joerg T. .
FUTURE NEUROLOGY, 2012, 7 (01) :93-111
[2]
Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death [J].
Arrasate, M ;
Mitra, S ;
Schweitzer, ES ;
Segal, MR ;
Finkbeiner, S .
NATURE, 2004, 431 (7010) :805-810
[3]
Iron Accumulates in Huntington's Disease Neurons: Protection by Deferoxamine [J].
Chen, Jianfang ;
Marks, Eileen ;
Lai, Barry ;
Zhang, Zhaojie ;
Duce, James A. ;
Lam, Linh Q. ;
Volitakis, Irene ;
Bush, Ashley I. ;
Hersch, Steven ;
Fox, Jonathan H. .
PLOS ONE, 2013, 8 (10)
[4]
PBT2 Reduces Toxicity in a C. elegans Model of polyQ Aggregation and Extends Lifespan, Reduces Striatal Atrophy and Improves Motor Performance in the R6/2 Mouse Model of Huntington's Disease [J].
Cherny, Robert A. ;
Ayton, Scott ;
Finkelstein, David I. ;
Bush, Ashley I. ;
McColl, Gawain ;
Massa, Stephen M. .
JOURNAL OF HUNTINGTONS DISEASE, 2012, 1 (02) :211-219
[5]
A small-molecule therapeutic lead for Huntington's disease: Preclinical pharmacology and efficacy of C2-8 in the R6/2 transgenic mouse [J].
Chopra, Vanita ;
Fox, Jonathan H. ;
Lieberman, Greg ;
Dorsey, Kathryn ;
Matson, Wayne ;
Waldmeier, Peter ;
Housman, David E. ;
Kazantsev, Aleksey ;
Young, Anne B. ;
Hersch, Steven .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (42) :16685-16689
[6]
Extrapolating brain development from experimental species to humans [J].
Clancy, Barbara ;
Finlay, Barbara L. ;
Darlington, Richard B. ;
Arland, K. J. S. .
NEUROTOXICOLOGY, 2007, 28 (05) :931-937
[7]
Iron Homeostasis in the Neonate [J].
Collard, Keith J. .
PEDIATRICS, 2009, 123 (04) :1208-1216
[8]
Transcriptional repression of PGC-α by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration [J].
Cui, Libin ;
Jeong, Hyunkyung ;
Borovecki, Fran ;
Parkhurst, Christopher N. ;
Tanese, Naoko ;
Krainc, Dimitri .
CELL, 2006, 127 (01) :59-69
[9]
Selegiline protects against recognition memory impairment induced by neonatal iron treatment [J].
de Lima, MNM ;
Laranja, DC ;
Caldana, F ;
Grazziotin, MM ;
Garcia, VA ;
Dal-Pizzol, F ;
Bromberg, E ;
Schröder, N .
EXPERIMENTAL NEUROLOGY, 2005, 196 (01) :177-183
[10]
ALTERATIONS IN THE LEVELS OF IRON, FERRITIN AND OTHER TRACE-METALS IN PARKINSONS-DISEASE AND OTHER NEURODEGENERATIVE DISEASES AFFECTING THE BASAL GANGLIA [J].
DEXTER, DT ;
CARAYON, A ;
JAVOYAGID, F ;
AGID, Y ;
WELLS, FR ;
DANIEL, SE ;
LEES, AJ ;
JENNER, P ;
MARSDEN, CD .
BRAIN, 1991, 114 :1953-1975