iScience (Jan 2023)

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

Journal volume & issue
Vol. 26, no. 1
p. 105885

Abstract

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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.

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