Preprint / Version 1

Loss of Tousled-Like Kinase 2 Reduces Antioxidative Responses and Disrupts Brain Development

This article is a preprint and has not been certified by peer review.

Authors

    Qiannan Deng,  
    Qiannan Deng
    Fanjia Hou,  
    Fanjia Hou
    Xiaoqi Zhou,  
    Xiaoqi Zhou
    Yiwen Zhang,  
    Yiwen Zhang
    • Zhejiang University School of Medicine Children's Hospital
    Qing Zhang,  
    Qing Zhang
    Jiaqi Zhang,  
    Jiaqi Zhang
    • Chongqing Medical University
    Zihan Zhang,  
    Zihan Zhang
    Tongfei Liu,  
    Tongfei Liu
    • Chongqing Medical University
    Wen Yuan,  
    Wen Yuan
    Chaochun Zou,  
    Chaochun Zou
    • Zhejiang University School of Medicine Children's Hospital
    Chao Tong,  
    Chao Tong
    Ke Zhang
    Ke Zhang
Categories
Neuroscience & Neurology
Keywords
TLK2; rare neurodevelopmental disorder; microcephaly; oxidative stress

Abstract

Haploinsufficiency of tousled-like kinase 2 (TLK2) causes intellectual developmental disorder, autosomal dominant 57, a rare neurodevelopmental disorder with unclear pathomechanism and no effective treatment. Here, we established Drosophila models with neurodevelopmental defects resembling some disease features, such as microcephaly. Further studies suggested that oxidative stress plays a critical role in these models. Mechanistically, Tlk (the fly homolog of TLK2) loss reduces the expression of antioxidative genes via activating transcription factor 4 (ATF4) and its downstream protein, nuclear factor erythroid 2-related factor 2 (Nrf2), a transcriptional activator of antioxidative genes, in fly neural stem cells (NSCs), thereby disrupting NSC differentiation and causing microcephaly. In patient-derived brain organoids, ATF4, Nrf2, and their downstream antioxidative genes are also downregulated. Agreeing with these data, these organoids exhibited oxidative stress and microcephaly. Combined, our findings suggest that ATF4/Nrf2-mediated antioxidative stress responses play a critical role in TLK2-related disease and may be a therapeutic target.

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DOI:

https://doi.org/10.65215/LTSpreprints.2026.03.06.000145

Submission ID:

145

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Posted

2026-03-07

How to Cite

Deng, Q., Hou, F., Zhou, X., Zhang, Y., Zhang, Q., Zhang, J., Zhang, Z., Liu, T., Yuan, W., Zou, C., Tong, C., & Zhang, K. (2026). Loss of Tousled-Like Kinase 2 Reduces Antioxidative Responses and Disrupts Brain Development. LangTaoSha Preprint Server. https://doi.org/10.65215/LTSpreprints.2026.03.06.000145

Declaration of Competing Interests

The authors declare no competing interests to disclose.

Copyright

The copyright holder for this preprint is the author/funder.

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.