Autophagosome maturation mediated by Rab7 contributes to neuroprotection of hypoxic preconditioning against global cerebral ischemia in rats

• Type of Material: Article
• Authors: Lixuan Zhan, Rollins School of Public Health; Siyuan Chen, Rollins School of Public Health; Kongping Li, Rollins School of Public Health; Donghai Liang, Emory University; Xinyong Zhu, Rollins School of Public Health; Liu Liu, Rollins School of Public Health; Zhiwei Lu, Rollins School of Public Health; Weiwen Sun, Rollins School of Public Health; En Xu, Rollins School of Public Health
• Language: English
• Date: 2017-07-20
• Publisher: Springer Nature
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2017 The Author(s)
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/cddis.2017.330
• Title of Journal or Parent Work: Cell Death and Disease
• Volume: 8
• Issue: 7
• Start Page: e2949
• End Page: e2949
• Grant/Funding Information: This work is supported by the National Natural Science Foundation of China (Grant No. 81571140), Natural Science Foundation of Guangdong, China (No. 2015A030313461), Project of Science and Technology Program of Guangzhou Bureau of Education, China (No. 1201410359), and the Science and Technology Program of Guangzhou, China (Grant No. 201510010118).
• Keywords: rab GTP-Binding Proteins; Neuroprotection; Autophagosomes; Rats, Wistar; Ischemic Preconditioning; Rats; Brain Ischemia; CA1 Region, Hippocampal; Animals; Male
• Research Categories: Biology, Neuroscience; Biology, Cell; Environmental Sciences; Health Sciences, Public Health

Abstract

Autophagy disruption leads to neuronal damage in hypoxic-ischemic brain injury. Rab7, a member of the Rab GTPase superfamily, has a unique role in the regulation of autophagy. Hypoxic preconditioning (HPC) provides neuroprotection against transient global cerebral ischemia (tGCI). However, the underlying mechanisms remain poorly understood. Thus, the current study explored the potential molecular mechanism of the neuroprotective effect of HPC by investigating how Rab7 mediates autophagosome (AP) maturation after tGCI in adult rats. We found that HPC attenuated AP accumulation in the hippocampal CA1 region after tGCI via restoration of autophagic flux. We also confirmed that this HPC-induced neuroprotection was not caused by the increase in lysosomes or the improvement of lysosomal function after tGCI. Electron microscopic analysis then revealed an increase in autolysosomes in CA1 neurons of HPC rats. Moreover, the inhibition of autophagosome-lysosome fusion by chloroquine significantly aggravated neuronal death in CA1, indicating that AP maturation contributes to HPC-induced neuroprotection against neuronal injury after tGCI. Furthermore, the activation of Rab7 was found to be involved in the neuroprotective effect of AP maturation after HPC. At last, the knockdown of ultraviolet radiation resistance-associated gene (UVRAG) in vivo disrupted the interaction between Vps16 and Rab7, attenuated the activation of Rab7, interrupted autophagic flux, and ultimately abrogated the HPC-induced neuroprotection against tGCI. Our results indicated that AP maturation was enhanced by the activation of Rab7 via UVRAG-Vps16 interaction, which further demonstrated the potential neuroprotective role of Rab7 in HPC against tGCI-induced neuronal injury in adult rats.