Rac1 conditional deletion attenuates retinal ganglion cell apoptosis by accelerating autophagic flux in a mouse model of chronic ocular hypertension
| Autor: | Guo-Li Zhao, Shu-Min Zhong, Fang Li, Lin-Jie Xu, Zhongfeng Wang, Fei Yuan, Wei-Ran Niu, Yu Hou, Meng-Lu Zhang, Yanying Miao, Xiong-Li Yang |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Retinal Ganglion Cells rac1 GTP-Binding Protein Cancer Research Programmed cell death genetic structures Autolysosome Immunology Apoptosis Article Retina Cellular and Molecular Neuroscience Mice Conditional gene knockout medicine Autophagy Animals Humans lcsh:QH573-671 PI3K/AKT/mTOR pathway Chemistry lcsh:Cytology Cell Differentiation Cell Biology Autophagy-related protein 13 Peptide Fragments eye diseases Cell biology Disease Models Animal medicine.anatomical_structure Retinal ganglion cell Chronic Disease Ocular Hypertension sense organs |
| Zdroj: | Cell Death & Disease Cell Death and Disease, Vol 11, Iss 9, Pp 1-13 (2020) |
| ISSN: | 2041-4889 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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