Increased optic atrophy type 1 expression protects retinal ganglion cells in a mouse model of glaucoma
Increased optic atrophy type 1 expression protects retinal ganglion cells in a mouse model of glaucoma
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发表时间：
2010-07
期刊：
影响因子：
2.2
通讯作者：
W. Ju;Keun-Young Kim;Karen X. Duong-Polk;J. Lindsey;Mark Ellisman;R. Weinreb
中科院分区：
文献类型：
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作者：
W. Ju;Keun-Young Kim;Karen X. Duong-Polk;J. Lindsey;Mark Ellisman;R. Weinreb
目的探讨视神经萎缩1型(OPA1)表达增加对青光眼DBA/2J小鼠视网膜神经节细胞(RGC)死亡的保护作用。方法测量DBA/2J小鼠的眼压，将含AAV2-野生型(WT)mOPA1的重组腺相关病毒2型(AAV2)基因导入青光眼前期DBA/2J小鼠的眼内，连续2个月。Western blotting证实OPA1表达增加，荧光金逆行标记评估RGC存活。此外，AAV2-WT mOPA1基因转染的分化RGC-5细胞在高压(30 Mm Hg)作用3天后，可检测到细胞凋亡和线粒体结构。结果WT AAV2-mOPA1基因可显著增加青光眼DBA/2J小鼠视网膜中90 kDa和80 kDa OPA1亚型的表达。9月龄青光眼DBA/2J小鼠AAV2-WT mOPA1表达增强，内核层、内丛状层和神经节细胞层的OPA1免疫反应增强。AAV2-WT mOPA1过表达可显著提高AAV2-WT mOPA1转基因小鼠视网膜RGC的存活率，降低星形胶质细胞和小胶质细胞的活化程度。此外，在分化的RGC-5细胞中过表达OPA1导致较少的细胞凋亡，并阻止了静水压力升高后线粒体的分裂。结论OPA1可直接调节RGC存活，增加OPA1表达可能对青光眼视神经病变RGC死亡有保护作用。
Purpose The goal of this study is to determine whether increased optic atrophy type 1 (OPA1) expression protects against retinal ganglion cell (RGC) death in glaucomatous DBA/2J mice. Methods Intraocular pressure in DBA/2J mice was measured, and pre-glaucomatous DBA/2J mice eyes were transfected with recombinant adeno-associated virus serotype 2 (AAV2) constructs including AAV2-wild type (WT) mOPA1 for two months. Increased OPA1 expression was confirmed by western blotting and RGC survival was assessed by retrograde labeling with FluoroGold. In addition, apoptotic cell death and mitochondrial structure were determined in AAV2-WT mOPA1-transfected differentiated RGC-5 cells exposed to elevated hydrostatic pressure (30 mmHg) for three days. Results WT AAV2-mOPA1 transfection significantly increased 90 kDa and 80 kDa OPA1 isoforms in the retina of glaucomatous DBA/2J mice. OPA1 immunoreactivity was increased in the inner nuclear layer, inner plexiform layer, and ganglion cell layer in nine month-old glaucomatous DBA/2J mice transfected with AAV2-WT mOPA1. Overexpression of OPA1 significantly increased RGC survival at two months after AAV2-WT mOPA1 transfection, and decreased activation of both astroglia and microglia in the retina of glaucomatous DBA/2J mice. Also, overexpression of OPA1 in differentiated RGC-5 cells resulted in less apoptotic cell death and blocked mitochondrial fission following elevated hydrostatic pressure. Conclusions OPA1 can directly modulate RGC survival, and increasing OPA1 expression may protect against RGC death in glaucomatous optic neuropathy.