中国神经再生研究(英文版) ›› 2025, Vol. 20 ›› Issue (11): 3233-3244.doi: 10.4103/NRR.NRR-D-24-00113

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

MAP4K 的 Citron 同源结构域可改善创伤性脑损伤的治疗效果

  

  • 出版日期:2025-11-15 发布日期:2025-02-25

The Citron homology domain of MAP4Ks improves outcomes of traumatic brain injury

Xiaoling Zhong1, 2, Wenjiao Tai1, 2, Meng-Lu Liu1 , Shuaipeng Ma1, 2, Tianjin Shen1, 2, Yuhua Zou1, 2, Chun-Li Zhang1, 2, 3, *   

  1. 1 Department of Molecular Biology,  2 Hamon Center for Regenerative Science and Medicine,  3 Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
  • Online:2025-11-15 Published:2025-02-25
  • Contact: Chun-Li Zhang, PhD, Chun-Li.Zhang@UTSouthwestern.edu.
  • Supported by:
    CLZ is a W.W. Caruth, Jr. Scholar in Biomedical Research and supported by the TARCC, Welch Foundation Award (I-1724), the Decherd Foundation, the Pape Adams Foundation, and NIH grants NS092616, NS127375, NS117065, and NS111776.

摘要:

丝裂原活化蛋白激酶激酶(MAP4Ks)信号通路在轴突再生和损伤后神经元变性中发挥着关键作用。靶向这一通路是否有益于脑损伤仍不清楚。实验发现通过腺相关病毒递送 MAP4Ks 的 Citron 同源结构域,可以有效减少创伤性脑损伤引起的反应性胶质细胞增多、tauopathy、病变大小和行为障碍。对 MAP4Ks 的药理抑制复制了通过表达 Citron 同源结构域观察到的改善效果。作用机制为香橼同源域作为显性阴性突变体,阻碍了MAP4K介导的散乱蛋白磷酸化,从而控制了Wnt/β-catenin通路。这些发现揭示了靶向 MAP4Ks 的治疗潜力可减轻创伤性脑损伤的有害影响。

https://orcid.org/0000-0002-2639-4605 (Chun-Li Zhang)

Abstract: The mitogen-activated protein kinase kinase kinase kinases (MAP4Ks) signaling pathway plays a pivotal role in axonal regrowth and neuronal degeneration following insults. Whether targeting this pathway is beneficial to brain injury remains unclear. In this study, we showed that adeno-associated virus-delivery of the Citron homology domain of MAP4Ks effectively reduces traumatic brain injury-induced reactive gliosis, tauopathy, lesion size, and behavioral deficits. Pharmacological inhibition of MAP4Ks replicated the ameliorative effects observed with expression of the Citron homology domain. Mechanistically, the Citron homology domain acted as a dominant-negative mutant, impeding MAP4K-mediated phosphorylation of the dishevelled proteins and thereby controlling the Wnt/β-catenin pathway. These findings implicate a therapeutic potential of targeting MAP4Ks to alleviate the detrimental effects of traumatic brain injury.

Key words: adeno-associated virus, Citron homology, Citron homology domain, gene therapy, mitogen-activated protein kinase kinase kinase kinases, traumatic brain injury