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Advanced Neurology

ORIGINAL RESEARCH ARTICLE
TDP43 negatively regulates TBK1-mediated

IFN1 production through IRF7 pathway in
neurodegenerative diseases

2
3
2
Wenjuan Zhang , Zhen Yi , Daihe Yang , Yifan Hao , Feng Zhou 4 ,
1
Guohua Song , Cao Huang * , Yun Zhou *, and Bo Huang 3,6,7,8,9 *
2
6
5
1 Department of Neurology, Innovation Research Institute of Traditional Chinese Medicine, Shandong
University of Traditional Chinese Medicine, Jinan, Shandong, China
2 Department of Nephrology, Shanxi Medical University, Taiyuan, Shanxi, China
3 Department of Anesthesiology, the Affiliated Second People’s Hospital of Fujian University of
Traditional Chinese Medicine, Fuzhou, Fujian, China
4 Department of Neurology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China
5 Department of Pathology, Thomas Jefferson University, 1020 Locust Street, Philadelphia,
Pennsylvania, United States of America
6 Department of Nephrology, First Hospital of Shangxi Medical University, Taiyuan, Shanxi, China
7 Medical Sciences, UCSI University, Kuala Lumpur, Malaysia
8 Department of Nephrology, Shanxi University of Chinese Medicine, Taiyuan, Shanxi, China
9 Laboratory Animal Center, The Fifth Hospital (Shanxi Provincial People’s Hospital) of Shanxi
Medical University, Taiyuan, Shanxi, China
*Corresponding authors:
Cao Huang
(caohuang777@yahoo.com)
Zhou Yun Abstract
(zhouyun_sx@163.com)
Bo Huang Mutations in the genes encoding TAR DNA-binding protein 43 (TDP43) or TANK-
(langlang@sxmu.edu.cn) binding kinase 1 (TBK1) have been strongly associated with neurological disorders,
Citation: Zhang W, Yi Z, Yang, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. TDP43
et al. TDP43 negatively regulates is a key component of pathological protein aggregates found in more than 90% of
TBK1-mediated IFN1 production
through IRF7 pathway in ALS cases, while TBK1 plays a critical role in innate immune signaling and autophagy.
neurodegenerative disease. Adv Despite these associations, the precise molecular mechanisms linking TDP43 or TBK1
Neurol. 2025;4(1):94-104. dysfunction to neurodegeneration remain poorly understood. The present study
doi: 10.36922/an.6272
examined the impact of TDP43 on TBK1-mediated type I interferon (IFN1) production
Received: November 19, 2024 in HEK-293T cells. The findings demonstrated that co-expression of TDP43 and TBK1
Revised: January 6, 2025 resulted in a dose-dependent reduction in TBK1 and interferon regulatory factor (IRF)
7 protein levels. In addition, it led to decreased phosphorylation of IRF3 and TBK1.
Accepted: January 15, 2025
Interestingly, TDP43 knockout cells displayed elevated IRF7 protein levels. Moreover,
Published Online: February 7, co-expression of TDP43 and TBK1 significantly suppressed the IFN1 inductions and
2025
associated pro-inflammatory cytokines, a suppression reversed by IRF7 overexpression.
Copyright: © 2025 Author(s). Further, mechanistic analysis demonstrated that TDP43 facilitates TBK1 degradation
This is an Open-Access article through autophagy, resulting in diminished IFN1 induction. These findings uncover a
distributed under the terms of the
Creative Commons Attribution new pathway through which TDP43 disrupts TBK1-mediated signaling through IRF7,
License, permitting distribution, potentially contributing to neurodegeneration. Overall, the disrupted TBK1-IRF7-IFN1
and reproduction in any medium, axis may therefore represent a critical pathway in TDP43-associated neurodegenerative
provided the original work is
properly cited. diseases, offering potential targets for therapeutic intervention.
Publisher’s Note: AccScience
Publishing remains neutral with Keywords: Amyotrophic lateral sclerosis; TAR DNA-binding protein 43; TANK-binding
regard to jurisdictional claims in
published maps and institutional kinase 1; Type I interferons; Interferon regulatory factor 7
affiliations.

Volume 4 Issue 1 (2025) 94 doi: 10.36922/an.6272