ASK1 deficiency attenuates neural cell death in GLAST-deficient mice, a model of normal tension glaucoma
ASK1 deficiency attenuates neural cell death in GLAST-deficient mice, a model of normal tension glaucoma
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DOI：
10.1038/cdd.2010.62
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发表时间：
2010-11-01
影响因子：
12.4
通讯作者：
Harada, T.
中科院分区：
文献类型：
--
作者：
Harada, C.;Namekata, K.;Harada, T.
凋亡信号调节激酶1（ASK1）是一种进化上保守的丝裂原活化蛋白激酶（MAPK）激酶激酶，在应激诱导的视网膜神经节细胞（RGC）凋亡中具有重要作用。在哺乳动物视网膜中，谷氨酸/天冬氨酸转运体（GLAST）是一种主要的谷氨酸转运体，GLAST的缺失会导致类似于正常眼压性青光眼（NTG）的视神经退变。在GLAST（-/-）小鼠中，视网膜中的谷胱甘肽水平降低，这表明氧化应激参与了NTG的发病机制。为了验证这一假设，我们通过多焦视网膜电图检查了GLAST（+/-）：ASK1（-/-）和GLAST（-/-）：ASK1（-/-）小鼠的组织学和视觉功能。ASK1缺失保护了RGCs，并减少了视神经中退变轴突的数量。与这一发现一致的是，与GLAST（+/-）和GLAST（-/-）小鼠相比，GLAST（+/-）：ASK1（-/-）和GLAST（-/-）：ASK1（-/-）小鼠的视觉功能分别得到了显著改善。ASK1的缺失对视网膜中谷胱甘肽或丙二醛的产生以及眼内压没有影响。在ASK1缺失的米勒胶质细胞中，肿瘤坏死因子（TNF）诱导的p38 MAPK激活和诱导型一氧化氮合酶的产生受到抑制。此外，在ASK1缺失的RGCs中，TNF诱导的细胞死亡受到抑制。这些结果表明，ASK1的激活在神经细胞和胶质细胞中都参与了类似NTG的病理过程，并且阻断ASK1依赖的通路可能对青光眼（包括NTG）的治疗有益。《细胞死亡与分化》（2010年）17卷，1751 - 1759页；doi:10.1038/cdd.2010.62；2010年5月21日在线发表
Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase (MAPK) kinase kinase and has an important role in stress-induced retinal ganglion cell (RGC) apoptosis. In the mammalian retina, glutamate/ aspartate transporter (GLAST) is a major glutamate transporter, and the loss of GLAST leads to optic nerve degeneration similar to normal tension glaucoma (NTG). In GLAST(-/-) mice, the glutathione level in the retina is decreased, suggesting the involvement of oxidative stress in NTG pathogenesis. To test this hypothesis, we examined the histology and visual function of GLAST(+/-):ASK1(-/-) and GLAST(-/-) : ASK1(-/-) mice by multifocal electroretinograms. ASK1 deficiency protected RGCs and decreased the number of degenerating axons in the optic nerve. Consistent with this finding, visual function was significantly improved in GLAST(+/-):ASK1(-/-) and GLAST(-/-) : ASK1(-/-) mice compared with GLAST(+/-) and GLAST(-/-) mice, respectively. The loss of ASK1 had no effects on the production of glutathione or malondialdehyde in the retina or on the intraocular pressure. Tumor necrosis factor (TNF)-induced activation of p38 MAPK and the production of inducible nitric oxide synthase were suppressed in ASK1-deficient Muller glial cells. In addition, TNF-induced cell death was suppressed in ASK1-deficient RGCs. These results suggest that ASK1 activation is involved in NTG-like pathology in both neural and glial cells and that interrupting ASK1-dependent pathways could be beneficial in the treatment of glaucoma, including NTG. Cell Death and Differentiation (2010) 17, 1751-1759; doi:10.1038/cdd.2010.62; published online 21 May 2010