Symposium: Neurodegeneration with Brain Iron Accumulation
Symposium: Neurodegeneration with Brain Iron Accumulation
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DOI：
10.1111/neup.12149
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发表时间：
2015-02-01
期刊：
影响因子：
2.3
通讯作者：
Miyajima, Hiroaki
中科院分区：
文献类型：
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作者：
Miyajima, Hiroaki
青蓝纤溶蛋白血症的特点是由于青蓝纤溶蛋白基因突变导致的铜蓝纤溶蛋白氧化铁酶活性完全缺乏，导致进行性神经变性伴脑铁积累。在星形胶质细胞中，氧化还原活性铁积累比在神经元中更为突出。最典型的表现是星形胶质细胞异常或变形，星形胶质细胞呈球状结构。铜蓝蛋白的缺乏可能主要是由于大量铁沉积引起的脂质过氧化而损害急性铜蓝蛋白血症脑中的星形细胞。在正常的大脑中，铁可以在星形胶质细胞和神经元之间不断地循环，而转铁蛋白就像一个穿梭者。星形胶质细胞上的糖基磷脂酰肌醇（GPI）连接的铜蓝蛋白作为铁氧化酶起作用，介导由铁转运蛋白从细胞质运输的亚铁的氧化及其随后向转铁蛋白的转移。在铜蓝蛋白血症的病例中，神经元从非转铁蛋白结合的铁的替代来源摄取铁，因为没有gpi连接的铜蓝蛋白的星形细胞不能将铁转运到转铁蛋白。星形胶质细胞中过量的铁可能导致这些细胞氧化损伤，星形胶质细胞提供的神经细胞保护因此被破坏。早期的缺铁和晚期的铁介导氧化可能导致神经元细胞损失。因此，铜蓝蛋白可能在中枢神经系统的神经元存活中起重要作用。
Aceruloplasminemia is characterized by progressive neurodegeneration with brain iron accumulation due to the complete lack of ceruloplasmin ferroxidase activity caused by mutations in the ceruloplasmin gene. Redox-active iron accumulation was found to be more prominent in the astrocytes than in the neurons. The most characteristic findings were abnormal or deformed astrocytes and globular structures of astrocytes. The lack of ceruloplasmin may primarily damage astrocytes in the aceruloplasminemic brains as a result of lipid peroxidation due to massive iron deposition. In the normal brain, iron may be continuously recycled between astrocytes and neurons, with transferrin acting as a shuttle. The glycosylphosphatidylinositol (GPI)-linked ceruloplasmin on astrocytes functions as a ferroxidase, mediating the oxidation of ferrous iron transported from the cytosol by ferroportin and its subsequent transfer to transferrin. In cases with aceruloplasminemia, neurons take up the iron from alternative sources of non-transferrin-bound iron, because astrocytes without GPI-linked ceruloplasmin cannot transport iron to transferrin. The excess iron in astrocytes could result in oxidative damage to these cells, and the neuronal cell protection offered by astrocytes would thus be disrupted. Neuronal cell loss may result from iron starvation in the early stage and from iron-mediated oxidation in the late stage. Ceruloplasmin may therefore play an essential role in neuronal survival in the central nervous system.