Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (11): 3233-3244.doi: 10.4103/NRR.NRR-D-24-00113

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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.

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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