Rac1 conditional deletion attenuates retinal ganglion cell apoptosis by accelerating autophagic flux in a mouse model of chronic ocular hypertension. Cell Death & Disease 2020; 11: 734
Rac1 conditional deletion attenuates retinal ganglion cell apoptosis by accelerating autophagic flux in a mouse model of chronic ocular hypertension. Cell Death & Disease 2020; 11: 734
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在慢性高眼压小鼠模型中，Rac1 条件性缺失可通过加速自噬通量来减弱视网膜神经节细胞凋亡。
DOI：
10.1038/s41419-020-02951-7
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发表时间：
2020
影响因子：
9
通讯作者：
Miao Y
中科院分区：
文献类型：
--
作者：
Zhang ML;Zhao GL;Hou Y;Zhong SM;Xu LJ;Li F;Niu WR;Yuan F;Wang Z;Miao Y
自噬在维持细胞稳态中起着重要作用。虽然自噬与青光眼的病理有关，但它如何调节视网膜神经节细胞（RGC）损伤在很大程度上是未知的。在本研究中，我们发现慢性高眼压（COH）小鼠模型中RGCs发生双相自噬，并伴有Rho家族成员Rac1的激活。RGCs中的Rac1条件敲除（Rac1 cKO）除了抑制COH视网膜中自噬体数量的增加和自噬相关蛋白（Beclin1、LC3-II/I和p62）的表达外，还能减弱RGC的凋亡。LAMP1和LC3B的电镜和双免疫染色显示，Rac1 cKO加速了COH小鼠RGC轴突的自溶酶体融合。用3-甲基腺嘌呤或Atg13 siRNA抑制第一个自噬峰可减少RGC凋亡，而用3-MA抑制第二个自噬峰或氯喹阻断自噬通量可增加RGC凋亡。此外，Rac1 cKO减少了玻璃体内注射雷帕霉素诱导的自噬体和凋亡RGCs的数量，表明Rac1负性调节mTOR活性。此外，在COH视网膜中，Rac1的缺失降低了Bak的表达，并且不干扰Beclin1与Bcl-2或Bak的相互作用。综上所述，自噬在青光眼早期促进RGC细胞凋亡，在后期导致自噬细胞死亡。Rac1缺失通过mTOR/Beclin1-Bak调节自噬与凋亡的串扰，减轻RGC损伤。干扰Rac1/mTOR信号通路可能为青光眼的治疗提供新的策略。
Autophagy has a fundamental role in maintaining cell homeostasis. Although autophagy has been implicated in glaucomatous pathology, how it regulates retinal ganglion cell (RGC) injury is largely unknown. In the present work, we found that biphasic autophagy in RGCs occurred in a mouse model of chronic ocular hypertension (COH), accompanied by activation of Rac1, a member of the Rho family. Rac1 conditional knockout (Rac1 cKO) in RGCs attenuated RGC apoptosis, in addition to blocking the increase in the number of autophagosomes and the expression of autophagy-related proteins (Beclin1, LC3-II/I, and p62) in COH retinas. Electron micrograph and double immunostaining of LAMP1 and LC3B showed that Rac1 cKO accelerated autolysosome fusion in RGC axons of COH mice. Inhibiting the first autophagic peak with 3-methyladenine or Atg13 siRNA reduced RGC apoptosis, whereas inhibiting the second autophagic peak with 3-MA or blocking autophagic flux by chloroquine increased RGC apoptosis. Furthermore, Rac1 cKO reduced the number of autophagosomes and apoptotic RGCs induced by rapamycin injected intravitreally, which suggests that Rac1 negatively regulates mTOR activity. Moreover, Rac1 deletion decreased Bak expression and did not interfere with the interaction of Beclin1 and Bcl-2 or Bak in COH retinas. In conclusion, autophagy promotes RGC apoptosis in the early stages of glaucoma and results in autophagic cell death in later stages. Rac1 deletion alleviates RGC damage by regulating the cross talk between autophagy and apoptosis through mTOR/Beclin1-Bak. Interfering with the Rac1/mTOR signaling pathway may provide a new strategy for treating glaucoma.