Abnormal iron homeostasis and neurodegeneration.
Abnormal iron homeostasis and neurodegeneration.
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DOI：
10.3389/fnagi.2013.00032
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发表时间：
2013
影响因子：
4.8
通讯作者：
Vidal R
中科院分区：
文献类型：
--
作者：
Muhoberac BB;Vidal R
在许多神经退行性疾病中观察到异常的铁代谢，然而，只有两种显示脑铁稳态失调是神经退行性疾病的主要原因。在此，我们审查这些遗传性铁蛋白病（HF）或神经铁蛋白病，这是一种常染色体显性遗传，成人发病的退行性疾病引起的铁蛋白轻链（FTL）基因突变。HF具有以进行性运动障碍、行为障碍和认知损害为特征的临床表型。主要的病理发现是基底神经节的囊性空洞，铁蛋白包涵体（IB）的存在，和大量的铁沉积。突变的FTL亚基具有改变的序列和长度，但组装成可溶性24聚体，其在超微结构上与野生型的那些无区别。晶体学显示铁蛋白亚基之间通常微小的4倍孔的实质性局部破坏，因为C-末端解开成多个多肽构象。这种结构改变导致衰减的净铁掺入，导致细胞铁处理不当，铁蛋白聚集，和氧化损伤的铁和抗坏血酸盐的生理浓度。转基因鼠模型与HF的几个特征相似，包括进行性神经表型、铁蛋白IB形成和铁代谢失调。这些研究通过暗示（1）正常铁蛋白功能的丧失，其触发铁积累和铁蛋白多肽的过度产生，以及（2）通过自由基产生、铁蛋白聚集和氧化应激获得毒性功能，为HF的发病机制提供了工作假设。重要的是，铁蛋白聚集可以被铁螯合剂逆转，氧化损伤可以被自由基捕获抑制，这一发现可用于临床研究。这项工作为铁代谢异常在神经退行性变中的作用提供了新的见解。
Abnormal iron metabolism is observed in many neurodegenerative diseases, however, only two have shown dysregulation of brain iron homeostasis as the primary cause of neurodegeneration. Herein, we review one of these - hereditary ferritinopathy (HF) or neuroferritinopathy, which is an autosomal dominant, adult onset degenerative disease caused by mutations in the ferritin light chain (FTL) gene. HF has a clinical phenotype characterized by a progressive movement disorder, behavioral disturbances, and cognitive impairment. The main pathologic findings are cystic cavitation of the basal ganglia, the presence of ferritin inclusion bodies (IBs), and substantial iron deposition. Mutant FTL subunits have altered sequence and length but assemble into soluble 24-mers that are ultrastructurally indistinguishable from those of the wild type. Crystallography shows substantial localized disruption of the normally tiny 4-fold pores between the ferritin subunits because of unraveling of the C-termini into multiple polypeptide conformations. This structural alteration causes attenuated net iron incorporation leading to cellular iron mishandling, ferritin aggregation, and oxidative damage at physiological concentrations of iron and ascorbate. A transgenic murine model parallels several features of HF, including a progressive neurological phenotype, ferritin IB formation, and misregulation of iron metabolism. These studies provide a working hypothesis for the pathogenesis of HF by implicating (1) a loss of normal ferritin function that triggers iron accumulation and overproduction of ferritin polypeptides, and (2) a gain of toxic function through radical production, ferritin aggregation, and oxidative stress. Importantly, the finding that ferritin aggregation can be reversed by iron chelators and oxidative damage can be inhibited by radical trapping may be used for clinical investigation. This work provides new insights into the role of abnormal iron metabolism in neurodegeneration.