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自噬诱导外伤性视神经损伤后,mTORC2 激活通过 Akt 信号保护视网膜神经节细胞。

mTORC2 activation protects retinal ganglion cells via Akt signaling after autophagy induction in traumatic optic nerve injury.

机构信息

Institute of Eye Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.

Department of Ophthalmology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.

出版信息

Exp Mol Med. 2019 Aug 13;51(8):1-11. doi: 10.1038/s12276-019-0298-z.

DOI:10.1038/s12276-019-0298-z
PMID:31409770
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6802655/
Abstract

Traumatic optic neuropathy is an injury to the optic nerve that leads to vision loss. Autophagy is vital for cell survival and cell death in central nervous system injury, but the role of autophagy in traumatic optic nerve injury remains uncertain. Optic nerve crush is a robust model of traumatic optic nerve injury. p62 siRNA and rapamycin are autophagy inducers and have different neuroprotective effects in the central nervous system. In this study, p62 and rapamycin induced autophagy, but only p62 siRNA treatment provided a favorable protective effect in visual function and retinal ganglion cell (RGC) survival. Moreover, the number of macrophages at the optic nerve lesion site was lower in the p62-siRNA-treated group than in the other groups. p62 siRNA induced more M2 macrophage polarization than rapamycin did. Rapamycin inhibited both mTORC1 and mTORC2 activation, whereas p62 siRNA inhibited only mTORC1 activation and maintained mTORC2 and Akt activation. Inhibition of mTORC2-induced Akt activation resulted in blood-optic nerve barrier disruption. Combined treatment with rapamycin and the mTORC2 activator SC79 improved RGC survival. Overall, our findings suggest that mTORC2 activation after autophagy induction is necessary for the neuroprotection of RGCs in traumatic optic nerve injury and may lead to new clinical applications.

摘要

创伤性视神经病变是一种导致视力丧失的视神经损伤。自噬对于中枢神经系统损伤中的细胞存活和细胞死亡至关重要,但自噬在创伤性视神经损伤中的作用仍不确定。视神经钳夹是创伤性视神经损伤的强有力模型。p62 siRNA 和雷帕霉素是自噬诱导剂,在中枢神经系统中具有不同的神经保护作用。在这项研究中,p62 和雷帕霉素诱导了自噬,但只有 p62 siRNA 处理在视觉功能和视网膜神经节细胞 (RGC) 存活方面提供了有利的保护作用。此外,在 p62-siRNA 处理组中,视神经损伤部位的巨噬细胞数量低于其他组。p62 siRNA 诱导的 M2 巨噬细胞极化比雷帕霉素多。雷帕霉素抑制 mTORC1 和 mTORC2 的激活,而 p62 siRNA 仅抑制 mTORC1 的激活并维持 mTORC2 和 Akt 的激活。抑制 mTORC2 诱导的 Akt 激活导致血视神经屏障破坏。雷帕霉素和 mTORC2 激活剂 SC79 的联合治疗改善了 RGC 的存活。总的来说,我们的研究结果表明,自噬诱导后 mTORC2 的激活对于创伤性视神经损伤中 RGC 的神经保护是必要的,并且可能导致新的临床应用。

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