Glaucoma is an age-related neurodegenerative disease characterized by the progressive loss of retinal ganglion cells (RGCs). Chronic ocular hypertension, an important risk factor for glaucoma, leads to RGC axonal injury at the optic nerve head. This insult triggers molecularly distinct cascades governing RGC somal apoptosis and axonal degeneration. The molecular mechanisms activated by ocular hypertensive insult that drive both RGC somal apoptosis and axonal degeneration are incompletely understood. The cellular response to endoplasmic reticulum stress and induction of pro-apoptotic DNA damage inducible transcript 3 (DDIT3, also known as CHOP) have been implicated as drivers of neurodegeneration in many disease models, including glaucoma. RGCs express DDIT3 after glaucoma-relevant insults, and importantly, DDIT3 has been shown to contribute to both RGC somal apoptosis and axonal degeneration after acute induction of ocular hypertension. However, the role of DDIT3 in RGC somal and axonal degeneration has not been critically tested in a model of age-related chronic ocular hypertension. Here, we investigated the role of DDIT3 in glaucomatous RGC death using an age-related, naturally occurring ocular hypertensive mouse model of glaucoma, DBA/2J mice (D2). To accomplish this, a null allele of Ddit3 was backcrossed onto the D2 background. Homozygous Ddit3 deletion did not alter gross retinal or optic nerve head morphology, nor did it change the ocular hypertensive profile of D2 mice. In D2 mice, Ddit3 deletion conferred mild protection to RGC somas, but did not significantly prevent RGC axonal degeneration. Together, these data suggest that DDIT3 plays a minor role in perpetuating RGC somal apoptosis caused by chronic ocular hypertension-induced axonal injury, but does not significantly contribute to distal axonal degeneration.

青光眼是一种与年龄有关的神经退行性疾病，其特征在于视网膜神经节细胞（RGC）的逐渐丧失。慢性高眼压是青光眼的重要危险因素，会导致视神经头部的RGC轴突损伤。这种侮辱触发了控制RGC体细胞凋亡和轴突变性的分子独特的级联反应。尚不完全了解由眼高压损伤激活的既驱动RGC体细胞凋亡又发生轴突变性的分子机制。在包括青光眼在内的许多疾病模型中，细胞对内质网应激的反应和促凋亡DNA损伤诱导转录本3（DDIT3，也称为CHOP）的诱导已被认为是神经退行性疾病的驱动因素。RGC在与青光眼有关的损伤后表达DDIT3，重要的是，已显示DDIT3在急性诱发高眼压后对RGC体细胞凋亡和轴突变性均起作用。但是，尚未在年龄相关的慢性高眼压模型中严格测试DDIT3在RGC体细胞和轴突变性中的作用。在这里，我们使用年龄相关的，自然发生的青光眼，DBA / 2J小鼠（D2）年龄相关的自然发生的眼高压小鼠模型，研究了DDIT3在青光眼性RGC死亡中的作用。要做到这一点，需要一个无效的等位基因 青光眼的天然存在的眼部高血压小鼠模型，DBA / 2J小鼠（D2）。要做到这一点，需要一个无效的等位基因 青光眼的天然存在的眼部高血压小鼠模型，DBA / 2J小鼠（D2）。要做到这一点，需要一个无效的等位基因Ddit3回交到D2背景上。纯合的Ddit3缺失并没有改变大眼视网膜或视神经头的形态，也没有改变D2小鼠的眼部高血压特征。在D2小鼠中，Ddit3缺失为RGC体细胞赋予了轻度保护，但并未显着阻止RGC轴突变性。总之，这些数据表明，DDIT3在使慢性高眼压诱发的轴突损伤所致的RGC体细胞凋亡中起次要作用，但对远端轴突变性没有明显作用。