Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis.
Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis.
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DOI：
10.1523/jneurosci.4099-08.2008
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发表时间：
2008-12-10
期刊：
影响因子：
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通讯作者：
Johnson JA
中科院分区：
文献类型：
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作者：
Vargas MR;Johnson DA;Sirkis DW;Messing A;Johnson JA
星形胶质细胞中转录因子Nrf 2的激活协调抗氧化防御的上调并赋予对邻近神经元的保护。Cu/Zn-超氧化物歧化酶（SOD 1）的显性突变导致家族性肌萎缩侧索硬化症（ALS），这是一种以运动神经元进行性丧失为特征的致命疾病。非神经元细胞，包括星形胶质细胞，塑造ALS中的运动神经元存活，并且是预防运动神经元变性的潜在靶点。Nrf 2活化在星形胶质细胞中的保护作用从未在慢性神经变性模型中进行过研究。我们使用胶质细胞酸性蛋白（GFAP）启动子在星形胶质细胞中选择性过表达Nrf 2的转基因小鼠。表达ALS连锁突变体hSOD 1的星形胶质细胞对共培养运动神经元的毒性可通过Nrf 2过表达逆转。运动神经元的保护依赖于星形胶质细胞谷胱甘肽分泌的增加。通过将GFAP-Nrf 2小鼠与两种ALS小鼠模型杂交也观察到这种保护作用。星形胶质细胞中Nrf 2的过表达显著延迟发病和延长存活。这些发现表明星形胶质细胞中的Nrf 2活化是预防慢性神经变性的可行治疗靶点。
Activation of the transcription factor Nrf2 in astrocytes coordinates the up-regulation of antioxidant defenses and confers protection to neighboring neurons. Dominant mutations in Cu/Zn-superoxide dismutase (SOD1) cause familial forms of amyotrophic lateral sclerosis (ALS), a fatal disorder characterized by the progressive loss of motor neurons. Non-neuronal cells, including astrocytes, shape motor neuron survival in ALS and are a potential target to prevent motor neuron degeneration. The protective effect of Nrf2 activation in astrocytes has never been examined in a chronic model of neurodegeneration. We generated transgenic mice over-expressing Nrf2 selectively in astrocytes using the glial fibrillary acidic protein (GFAP) promoter. The toxicity of astrocytes expressing ALS-linked mutant hSOD1 to co-cultured motor neurons was reversed by Nrf2 over-expression. Motor neuron protection depended on increased glutathione secretion from astrocytes. This protective effect was also observed by crossing the GFAP-Nrf2 mice with two ALS-mouse models. Over-expression of Nrf2 in astrocytes significantly delayed onset and extended survival. These findings demonstrate that Nrf2 activation in astrocytes is a viable therapeutic target to prevent chronic neurodegeneration.