Abnormal iron metabolism and oxidative stress in mice expressing a mutant form of the ferritin light polypeptide gene.
Abnormal iron metabolism and oxidative stress in mice expressing a mutant form of the ferritin light polypeptide gene.
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DOI：
10.1111/j.1471-4159.2009.06028.x
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发表时间：
2009-05
影响因子：
4.7
通讯作者：
Vidal R
中科院分区：
文献类型：
--
作者：
Barbeito AG;Garringer HJ;Baraibar MA;Gao X;Arredondo M;Núñez MT;Smith MA;Ghetti B;Vidal R
铁蛋白轻链(FTL)基因外显子4的插入突变与遗传性铁蛋白病(HF)或神经铁蛋白病相关，后者是一种常染色体显性遗传性神经退行性疾病，其特征是进行性运动和认知功能障碍。为了确定FTL基因突变导致神经变性的致病机制，我们研究了表达突变的人FTL498-499InsTC基因的转基因(TG)小鼠脑内的铁代谢和氧化应激标志物。与野生型小鼠相比，TG(FTL-TG)小鼠脑提取液中FTL和铁蛋白重链多肽的胞浆水平均升高，转铁蛋白受体-1的蛋白和mRNA水平降低，铁水平显著升高。转基因小鼠还显示出大脑中存在脂质过氧化、蛋白质羰基和硝酮-蛋白质加合物的标记。然而，铁管理蛋白在TG小鼠肝脏中的基因表达分析表明，FTL-TG小鼠肝脏缺铁。我们的数据表明，脑内铁代谢的紊乱在HF的神经退变过程中起着主要作用，HF的发病机制可能是铁储存功能降低和与铁诱导的脑内铁蛋白聚集体相关的毒性增强的综合结果。
Insertional mutations in exon 4 of the ferritin light chain (FTL) gene are associated with hereditary ferritinopathy (HF) or neuroferritinopathy, an autosomal dominant neurodegenerative disease characterized by progressive impairment of motor and cognitive functions. To determine the pathogenic mechanisms by which mutations in FTL lead to neurodegeneration, we investigated iron metabolism and markers of oxidative stress in the brain of transgenic (Tg) mice that express the mutant human FTL498-499InsTC cDNA. Compared with wild-type mice, brain extracts from Tg (FTL-Tg) mice showed an increase in the cytoplasmic levels of both FTL and ferritin heavy chain polypeptides, a decrease in the protein and mRNA levels of transferrin receptor-1, and a significant increase in iron levels. Transgenic mice also showed the presence of markers for lipid peroxidation, protein carbonyls, and nitrone–protein adducts in the brain. However, gene expression analysis of iron management proteins in the liver of Tg mice indicates that the FTL-Tg mouse liver is iron deficient. Our data suggest that disruption of iron metabolism in the brain has a primary role in the process of neurodegeneration in HF and that the pathogenesis of HF is likely to result from a combination of reduction in iron storage function and enhanced toxicity associated with iron-induced ferritin aggregates in the brain.
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影响因子：
4.2
作者：
CONNOR, JR;MENZIES, SL;MUFSON, EJ
通讯作者：
MUFSON, EJ
影响因子：
4.8
作者：
Picard, V;Epsztejn, S;Beaumont, C
通讯作者：
Beaumont, C
影响因子：
5.3
作者：
Cassina, Patricia;Cassina, Adriana;Radi, Rafael
通讯作者：
Radi, Rafael
影响因子：
2.9
作者：
Johansson, Sofia;Fuchs, Andrea;Ekstrom, Tomas J.
通讯作者：
Ekstrom, Tomas J.
影响因子：
64.5
作者：
MULLNER, EW;KUHN, LC
通讯作者：
KUHN, LC