Dysregulation of Iron Homeostasis in the CNS Contributes to Disease Progression in a Mouse Model of Amyotrophic Lateral Sclerosis
Dysregulation of Iron Homeostasis in the CNS Contributes to Disease Progression in a Mouse Model of Amyotrophic Lateral Sclerosis
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DOI：
10.1523/jneurosci.5443-08.2009
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发表时间：
2009-01-21
影响因子：
5.3
通讯作者：
David, Samuel
中科院分区：
文献类型：
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作者：
Jeong, Suh Young;Rathore, Khizr I.;David, Samuel
肌萎缩侧索硬化症（amyotrophiclateralsclerosis，ALS）是一种以脊髓运动神经元变性为特征的疾病，分为散发型和家族型。家族性ALS的一个原因是超氧化物歧化酶1（SOD 1）基因的错义突变。两种形式的ALS的CNS中均发生铁蓄积;然而，其对ALS发病机制的贡献尚不清楚。我们研究了铁在过表达人SOD 1（G37 R）突变体的转基因小鼠系中的作用。我们发现，多种机制可能是SOD 1（G37 R）转基因小鼠神经元和胶质细胞铁积累的基础。这些包括参与铁内流和细胞内铁感应的蛋白质的失调;继发于顺行轴突运输阻断的腹侧运动神经元中的铁积累;以及神经元和神经胶质中线粒体铁负荷增加。我们还表明，用铁螯合剂治疗SOD 1（G37 R）小鼠可延长寿命5周，并伴有脊髓运动神经元存活率增加和运动功能改善。这些数据表明，铁螯合剂治疗可能是有用的ALS的治疗。
Amyotrophic lateral sclerosis (ALS), characterized by degeneration of spinal motor neurons, consists of sporadic and familial forms. One cause of familial ALS is missense mutations in the superoxide dismutase 1 (SOD1) gene. Iron accumulation occurs in the CNS of both forms of ALS; however, its contribution to the pathogenesis of ALS is not known. We examined the role of iron in a transgenic mouse line overexpressing the human SOD1(G37R) mutant. We show that multiple mechanisms may underlie the iron accumulation in neurons and glia in SOD1(G37R) transgenic mice. These include dysregulation of proteins involved in iron influx and sensing of intracellular iron; iron accumulation in ventral motor neurons secondary to blockage of anterograde axonal transport; and increased mitochondrial iron load in neurons and glia. We also show that treatment of SOD1(G37R) mice with an iron chelator extends life span by 5 weeks, accompanied by increased survival of spinal motor neurons and improved locomotor function. These data suggest that iron chelator therapy might be useful for the treatment of ALS.