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

Shuang Jin; Xiangfeng Chen; Hanyu Zheng; Wanxiong Cai; Xurong Lin; Xiangxing Kong; Yingchun Ni; Jingjia Ye; Xiaodan Li; Luoan Shen; Binjie Guo; Zeinab Abdelrahman; Songlin Zhou; Susu Mao; Yaxian Wang; Chun Yao; Xiaosong Gu; Bin Yu; Zhiping Wang; Xuhua Wang

doi:10.1016/j.isci.2022.105885

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

iScience. 2022 Dec 26;26(1):105885. doi: 10.1016/j.isci.2022.105885. eCollection 2023 Jan 20.

Authors

Shuang Jin^{1

2

3}, Xiangfeng Chen^{1

2

3}, Hanyu Zheng^{1

2

3}, Wanxiong Cai^{1

2

3}, Xurong Lin^{1

2

3}, Xiangxing Kong^{1

2

3}, Yingchun Ni^{1

2

3}, Jingjia Ye^{2

3

4}, Xiaodan Li^{2

3

4}, Luoan Shen^{2

3}, Binjie Guo^{1

2

3}, Zeinab Abdelrahman^{1

2

3

4}, Songlin Zhou⁵, Susu Mao⁵, Yaxian Wang⁵, Chun Yao⁵, Xiaosong Gu⁵, Bin Yu⁵, Zhiping Wang^{2

3

4}, Xuhua Wang^{1

2

3

6

4}

Affiliations

¹ Department of Neurobiology and Department of Rehabilitation Medicine, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310003, P.R. China.
² Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, P.R. China.
³ NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, P.R. China.
⁴ Department of Neurobiology and Department of Orthopedics, 2nd Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310003, P.R. China.
⁵ Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong, Jiangsu 226001, P.R. China.
⁶ Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, P.R. China.

Abstract

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.

Keywords: Biological sciences; Molecular neuroscience; Neuroscience.