Circadian rhythm disorders are common characteristics of neurodegenerative diseases. The pathological aggregation of transactive response DNA-binding protein 43 (TDP-43) is associated with multiple neurodegenerative diseases, such as amyotrophic lateral sclerosis. However, the relationship between TDP-43 and circadian rhythm remains unknown. Here, we found that TDP-43 is rhythmically expressed both in vivo and in vitro. TDP-43 knockdown affected the expression of circadian genes, including BMAL1, CLOCK, CRY1, and PER2, and impaired autonomous circadian wheel behavior, cognitive functions, and balance abilities in mice. Furthermore, TDP-43 knockdown induced aberrant splicing of ubiquitin-specific peptidase 13 (USP13) and blocked USP13 rhythmic expression, enhancing the ubiquitination of BMAL1. Meanwhile, TDP-43 knockdown altered the rhythmic expression of phospho-AMPKα (Thr172) and platelet-type phosphofructokinase (PFKP), which may change cellular glucose uptake and ATP production. Our findings further the understanding of the role of TDP-43 dysfunction in circadian rhythm disruption in neurodegenerative diseases and provide new mechanistic evidence supporting the interaction between circadian rhythm disruption and neurodegeneration.
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April 09 2025
Rhythmic TDP-43 affects RNA splicing of USP13, resulting in alteration of BMAL1 ubiquitination
Jianlan Gu
,
Jianlan Gu
*
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing)
1Department of Biochemistry and Molecular Biology, School of Medicine, Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products,
Nantong University
, Nantong, China
Jianlan Gu: [email protected]
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Mingming Yang
,
Mingming Yang
*
(Investigation)
1Department of Biochemistry and Molecular Biology, School of Medicine, Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products,
Nantong University
, Nantong, China
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Liti Zhang
,
Liti Zhang
*
(Investigation, Validation, Visualization)
1Department of Biochemistry and Molecular Biology, School of Medicine, Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products,
Nantong University
, Nantong, China
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Yuxiao Liu
,
Yuxiao Liu
(Data curation, Software)
1Department of Biochemistry and Molecular Biology, School of Medicine, Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products,
Nantong University
, Nantong, China
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Ruolan Yan
,
Ruolan Yan
(Investigation)
1Department of Biochemistry and Molecular Biology, School of Medicine, Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products,
Nantong University
, Nantong, China
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Danmin Pan
,
Danmin Pan
(Validation)
2Department of Cell Biology,
School of Life Sciences, Nantong University
, Nantong, China
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Xiaowei Qian
,
Xiaowei Qian
(Project administration, Validation)
2Department of Cell Biology,
School of Life Sciences, Nantong University
, Nantong, China
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Hanjing Hu
,
Hanjing Hu
(Methodology)
1Department of Biochemistry and Molecular Biology, School of Medicine, Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products,
Nantong University
, Nantong, China
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Dandan Chu
,
Dandan Chu
(Resources)
1Department of Biochemistry and Molecular Biology, School of Medicine, Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products,
Nantong University
, Nantong, China
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Chen Hu
,
(Conceptualization, Investigation, Methodology, Project administration, Resources, Validation, Writing - review & editing)
3
Biomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology
, Zibo, China
Chen Hu: [email protected]
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Fei Liu
,
4Department of Neurochemistry, Inge Grundke-Iqbal Research Floor,
New York State Institute for Basic Research in Developmental Disabilities
, Staten Island, NY, USA
Fei Liu: [email protected]
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Hengxiang Cui
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing)
5Shanghai Key Laboratory of Psychotic Disorders,
Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
Correspondence to Hengxiang Cui (lead contact): [email protected]
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Jianlan Gu
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
*
1Department of Biochemistry and Molecular Biology, School of Medicine, Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products,
Nantong University
, Nantong, China
1Department of Biochemistry and Molecular Biology, School of Medicine, Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products,
Nantong University
, Nantong, China
1Department of Biochemistry and Molecular Biology, School of Medicine, Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products,
Nantong University
, Nantong, China
Yuxiao Liu
Data curation, Software
1Department of Biochemistry and Molecular Biology, School of Medicine, Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products,
Nantong University
, Nantong, China
Ruolan Yan
Investigation
1Department of Biochemistry and Molecular Biology, School of Medicine, Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products,
Nantong University
, Nantong, China
Danmin Pan
Validation
2Department of Cell Biology,
School of Life Sciences, Nantong University
, Nantong, China
Xiaowei Qian
Project administration, Validation
2Department of Cell Biology,
School of Life Sciences, Nantong University
, Nantong, China
Hanjing Hu
Methodology
1Department of Biochemistry and Molecular Biology, School of Medicine, Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products,
Nantong University
, Nantong, China
Dandan Chu
Resources
1Department of Biochemistry and Molecular Biology, School of Medicine, Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products,
Nantong University
, Nantong, China
Chen Hu
Conceptualization, Investigation, Methodology, Project administration, Resources, Validation, Writing - review & editing
3
Biomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology
, Zibo, China
4Department of Neurochemistry, Inge Grundke-Iqbal Research Floor,
New York State Institute for Basic Research in Developmental Disabilities
, Staten Island, NY, USA
Hengxiang Cui
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
5Shanghai Key Laboratory of Psychotic Disorders,
Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine
, Shanghai, China
Correspondence to Hengxiang Cui (lead contact): [email protected]
Fei Liu: [email protected]
Chen Hu: [email protected]
Jianlan Gu: [email protected]
*
J. Gu, M. Yang, and L. Zhang contributed equally to this paper.
Disclosures: The authors declare no competing interests exist.
Received:
May 24 2024
Revision Received:
November 20 2024
Accepted:
February 11 2025
Online ISSN: 1540-8140
Print ISSN: 0021-9525
Funding
Funder(s):
National Natural Science Foundation of China
- Award Id(s): 32171258,31870772
Funder(s):
Natural Science Foundation of Jiangsu Province
- Award Id(s): BK20211329
Funder(s):
Co-Innovation Center of Neuroregeneration
Funder(s):
Nantong University
© 2025 Gu et al.
2025
Gu et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Cell Biol (2025) 224 (5): e202405142.
Article history
Received:
May 24 2024
Revision Received:
November 20 2024
Accepted:
February 11 2025
Citation
Jianlan Gu, Mingming Yang, Liti Zhang, Yuxiao Liu, Ruolan Yan, Danmin Pan, Xiaowei Qian, Hanjing Hu, Dandan Chu, Chen Hu, Fei Liu, Hengxiang Cui; Rhythmic TDP-43 affects RNA splicing of USP13, resulting in alteration of BMAL1 ubiquitination. J Cell Biol 5 May 2025; 224 (5): e202405142. doi: https://doi.org/10.1083/jcb.202405142
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