TY - JOUR T1 - Unbalanced Regulation of Sec22b and Ykt6 Blocks Autophagosome Axonal Retrograde Flux in Neuronal Ischemia–Reperfusion Injury JF - The Journal of Neuroscience JO - J. Neurosci. SP - 5641 LP - 5654 DO - 10.1523/JNEUROSCI.2030-21.2022 VL - 42 IS - 28 AU - Haiying Li AU - Xiang Li AU - Zhongmou Xu AU - Jinxin Lu AU - Chang Cao AU - Wanchun You AU - Zhengquan Yu AU - Haitao Shen AU - Gang Chen Y1 - 2022/07/13 UR - http://www.jneurosci.org/content/42/28/5641.abstract N2 - Cerebral ischemia–reperfusion (I/R) injury in ischemic penumbra is accountable for poor outcome of ischemic stroke patients receiving recanalization therapy. Compelling evidence previously demonstrated a dual role of autophagy in stroke. This study aimed to understand the traits of autophagy in the ischemic penumbra and the potential mechanism that switches the dual role of autophagy. We found that autophagy induction by rapamycin and lithium carbonate performed before ischemia reduced neurologic deficits and infarction, while autophagy induction after reperfusion had the opposite effect in the male murine middle cerebral artery occlusion/reperfusion (MCAO/R) model, both of which were eliminated in mice lacking autophagy (Atg7flox/flox; Nestin-Cre). Autophagic flux determination showed that reperfusion led to a blockage of axonal autophagosome retrograde transport in neurons, which then led to autophagic flux damage. Then, we found that I/R induced changes in the protein levels of Sec22b and Ykt6 in neurons, two autophagosome transport-related factors, in which Sec22b significantly increased and Ykt6 significantly decreased. In the absence of exogenous autophagy induction, Sec22b knock-down and Ykt6 overexpression significantly alleviated autophagic flux damage, infarction, and neurologic deficits in neurons or murine exposed to cerebral I/R in an autophagy-dependent manner. Furthermore, Sec22b knock-down and Ykt6 overexpression switched the outcome of rapamycin posttreatment from deterioration to neuroprotection. Thus, Sec22b and Ykt6 play key roles in neuronal autophagic flux, and modest regulation of Sec22b and Ykt6 may help to reverse the failure of targeting autophagy induction to improve the prognosis of ischemic stroke.SIGNIFICANCE STATEMENT The highly polarized architecture of neurons with neurites presents challenges for material transport, such as autophagosomes, which form at the neurite tip and need to be transported to the cell soma for degradation. Here, we demonstrate that Sec22b and Ykt6 act as autophagosome porters and play an important role in maintaining the integrity of neuronal autophagic flux. Ischemia–reperfusion (I/R)-induced excess Sec22b and loss of Ykt6 in neurons lead to axonal autophagosome retrograde trafficking failure, autophagic flux damage, and finally neuronal injury. Facilitated axonal autophagosome retrograde transport by Sec22b knock-down and Ykt6 overexpression may reduce I/R-induced neuron injury and extend the therapeutic window of pharmacological autophagy induction for neuroprotection. ER -