Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes
Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes
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DOI：
10.1007/s11357-008-9050-7
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发表时间：
2008-12-01
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影响因子：
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通讯作者：
Lee, Hyoung-gon
中科院分区：
文献类型：
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作者：
Myung, Na-Hye;Zhu, Xiongwei;Lee, Hyoung-gon
组蛋白家族的磷酸化不仅是对细胞信号传导刺激的反应，也是细胞凋亡变化之前 DNA 损伤的重要指标。虽然星形细胞变性（包括 DNA 损伤）在阿尔茨海默病 (AD) 中已有报道，但其发病意义尚不清楚。为了澄清这一点，我们研究了 γ H2AX 的表达作为星形胶质细胞 DNA 损伤的证据，以阐明这些细胞在 AD 发病机制中的作用。为了响应染色体 DNA 双链断裂的形成，H2AX（一种 14-kDa 蛋白，H2A 组蛋白家族的成员，也是核小体结构的一部分）上的丝氨酸 139 快速磷酸化，生成 γ H2AX。使用免疫细胞化学技术，我们发现在 AD 中易受影响的区域（即海马区域和大脑皮层）星形胶质细胞中 γ H2AX 水平显着增加。这些结果表明星形胶质细胞含有 DNA 损伤，可能导致功能障碍，进而减少它们对神经元的支持。这些发现进一步明确了星形胶质细胞功能障碍在 AD 进展中的作用。
Phosphorylation of the histone family is not only a response to cell signaling stimuli, but also an important indicator of DNA damage preceding apoptotic changes. While astrocytic degeneration, including DNA damage, has been reported in Alzheimer disease ( AD), its pathogenetic significance is somewhat unclear. In an effort to clarify this, we investigated the expression of gamma H2AX as evidence of DNA damage in astrocytes to elucidate the role of these cells in the pathogenesis of AD. In response to the formation of double-stranded breaks in chromosomal DNA, serine 139 on H2AX, a 14-kDa protein that is a member of the H2A histone family and part of the nucleosome structure, becomes rapidly phosphorylated to generate gamma H2AX. Using immunocytochemical techniques, we found significantly increased levels of gamma H2AX in astrocytes in regions know to be vulnerable in AD, i.e., the hippocampal regions and cerebral cortex. These results suggest that astrocytes contain DNA damage, possibly resulting in functional disability, which in turn reduces their support for neurons. These findings further define the role of astrocyte dysfunction in the progression of AD.