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

Xiaoling Zhong; Wenjiao Tai; Meng-Lu Liu; Shuaipeng Ma; Tianjin Shen; Yuhua Zou; Chun-Li Zhang

doi:10.4103/NRR.NRR-D-24-00113

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

Neural Regen Res. 2025 Nov 1;20(11):3233-3244. doi: 10.4103/NRR.NRR-D-24-00113. Epub 2024 Sep 24.

Authors

Xiaoling Zhong^{1

2}, Wenjiao Tai^{1

2}, Meng-Lu Liu¹, Shuaipeng Ma^{1

2}, Tianjin Shen^{1

2}, Yuhua Zou^{1

2}, Chun-Li Zhang^{1

2

3}

Affiliations

¹ Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
² Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
³ Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.

PMID: 39314140
DOI: 10.4103/NRR.NRR-D-24-00113

Abstract

JOURNAL/nrgr/04.03/01300535-202511000-00027/figure1/v/2024-12-20T164640Z/r/image-tiff 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.