Downregulation of UBE4B promotes CNS axon regrowth and functional recovery after stroke

The limited intrinsic regrowth capacity of corticospinal axons impedes functional recovery after cortical stroke. Although the mammalian target of rapamycin (mTOR) and p53 pathways have been identified as the key intrinsic pathways regulating CNS axon regrowth, little is known about the key upstream...

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Published in:iScience 2023-01, Vol.26 (1), p.105885-105885, Article 105885
Main Authors: Jin, Shuang, Chen, Xiangfeng, Zheng, Hanyu, Cai, Wanxiong, Lin, Xurong, Kong, Xiangxing, Ni, Yingchun, Ye, Jingjia, Li, Xiaodan, Shen, Luoan, Guo, Binjie, Abdelrahman, Zeinab, Zhou, Songlin, Mao, Susu, Wang, Yaxian, Yao, Chun, Gu, Xiaosong, Yu, Bin, Wang, Zhiping, Wang, Xuhua
Format: Article
Language:English
Subjects:
Biological sciences
Molecular neuroscience
Neuroscience
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Summary:The limited intrinsic regrowth capacity of corticospinal axons impedes functional recovery after cortical stroke. Although the mammalian target of rapamycin (mTOR) and p53 pathways have been identified as the key intrinsic pathways regulating CNS axon regrowth, little is known about the key upstream regulatory mechanism by which these two major pathways control CNS axon regrowth. By screening genes that regulate ubiquitin-mediated degradation of the p53 proteins in mice, we found that ubiquitination factor E4B (UBE4B) represses axonal regrowth in retinal ganglion cells and corticospinal neurons. We found that axonal regrowth induced by UBE4B depletion depended on the cooperative activation of p53 and mTOR. Importantly, overexpression of UbV.E4B, a competitive inhibitor of UBE4B, in corticospinal neurons promoted corticospinal axon sprouting and facilitated the recovery of corticospinal axon-dependent function in a cortical stroke model. Thus, our findings provide a translatable strategy for restoring corticospinal tract-dependent functions after cortical stroke. [Display omitted] •Deregulation of UBE4B is sufficient in promoting CNS axon regrowth•UBE4B regulates CNS axon regrowth through p53 and KLHL22/mTOR dual pathways•Modulation of UBE4B pathway via UbV.E4B overexpression promotes CNS axon regrowth•CST sprouting induced by UbV.E4B mediates CST-dependent function recovery after stroke Biological sciences; Neuroscience; Molecular neuroscience
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2022.105885