Department of Ophthalmology, The Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS One. 2011 Mar 29;6(3):e17659. doi: 10.1371/journal.pone.0017659.
Glaucoma, the most frequent optic neuropathy, is a leading cause of blindness worldwide. Death of retinal ganglion cells (RGCs) occurs in all forms of glaucoma and accounts for the loss of vision, however the molecular mechanisms that cause RGC loss remain unclear. The pro-apoptotic molecule, Fas ligand, is a transmembrane protein that can be cleaved from the cell surface by metalloproteinases to release a soluble protein with antagonistic activity. Previous studies documented that constitutive ocular expression of FasL maintained immune privilege and prevented neoangeogenesis. We now show that FasL also plays a major role in retinal neurotoxicity. Importantly, in both TNFα triggered RGC death and a spontaneous model of glaucoma, gene-targeted mice that express only full-length FasL exhibit accelerated RGC death. By contrast, FasL-deficiency, or administration of soluble FasL, protected RGCs from cell death. These data identify membrane-bound FasL as a critical effector molecule and potential therapeutic target in glaucoma.
青光眼是最常见的视神经病变，是全球致盲的主要原因。所有类型的青光眼都会导致视网膜神经节细胞 (RGC) 的死亡，从而导致视力丧失，但导致 RGC 死亡的分子机制仍不清楚。促凋亡分子 Fas 配体是一种跨膜蛋白，可被金属蛋白酶从细胞表面切割释放出具有拮抗活性的可溶性蛋白。先前的研究记录表明，FasL 的组成型眼部表达维持了免疫特权并防止了新生血管形成。我们现在表明，FasL 在视网膜神经毒性中也起着重要作用。重要的是，在 TNFα 触发的 RGC 死亡和自发性青光眼模型中，仅表达全长 FasL 的基因靶向小鼠表现出加速的 RGC 死亡。相比之下，FasL 缺陷或可溶性 FasL 的给药可保护 RGC 免受细胞死亡。这些数据将膜结合 FasL 确定为青光眼的关键效应分子和潜在治疗靶点。
