1. Academic Validation
  2. Reduction of Autophagosome Overload Attenuates Neuronal Cell Death After Traumatic Brain Injury

Reduction of Autophagosome Overload Attenuates Neuronal Cell Death After Traumatic Brain Injury

  • Neuroscience. 2021 Apr 15;460:107-119. doi: 10.1016/j.neuroscience.2021.02.007.
Xingyun Quan 1 Li Song 1 Xiaomei Zheng 2 Shenjie Liu 1 Huaqiang Ding 3 Sijing Li 1 Guanghui Xu 1 Xin Li 1 Liang Liu 4
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, China.
  • 2 Department of Neurology, The Affiliated Hospital of Southwest Medical University, China.
  • 3 Department of Neurosurgery, The People 's Hospital of Chongqing Yubei, China.
  • 4 Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, China; Sichuan Clinical Research Center for Neurosurgery, China; Neurological Diseases and Brain Functions Laboratory, Clinical Medical Research Center of Southwest Medical University, China; Academician (Expert) Workstation of Sichuan Province, China. Electronic address: liulst@163.com.
Abstract

Previous studies have shown that alterations in autophagy-related proteins exist extensively after traumatic brain injury (TBI). However, whether Autophagy is enhanced or suppressed by TBI remains controversial. In our study, a controlled cortical impact was used to establish a model of moderate TBI in rats. We found that a significant increase in protein levels of LC3-II and SQSTM1 in the injured cortex group. However, there were no significant differences in protein levels of Vps34, Beclin-1, and phosphor-ULK1, which are the promoters of Autophagy. Lysosome dysfunction after TBI might lead to autophagosome accumulation. In addition, the highly specific Autophagy Inhibitor SAR405 administration reduced TBI-induced apoptosis-related protein cleaved Caspase-3 and cleaved caspase-9 levels in the ipsilateral cortex, as well as brain edema and neurological defects accessed by mNSS. Furthermore, chloroquine treatment reversed the beneficial effects of SAR405 by increasing the accumulation of autophagosomes. Finally, our data showed that Autophagy inhibition by Vps34 gene knockout method attenuated cell death after TBI. Our findings indicate that impaired autophagosome degradation is involved in the pathological reaction after TBI, and the inhibition of Autophagy contributes to attenuate neuronal cell death and functional defects.

Keywords

SAR405; VPS34; autophagosome; autophagy; neuronal cell death; traumatic brain injury.

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