2. Academic Validation
  3. Rhythmic TDP-43 affects RNA splicing of USP13, resulting in alteration of BMAL1 ubiquitination

Rhythmic TDP-43 affects RNA splicing of USP13, resulting in alteration of BMAL1 ubiquitination

  • J Cell Biol. 2025 May 5;224(5):e202405142. doi: 10.1083/jcb.202405142.
Jianlan Gu # 1,  Mingming Yang # 1,  Liti Zhang # 1,  Yuxiao Liu 1,  Ruolan Yan 1,  Danmin Pan 2,  Xiaowei Qian 2,  Hanjing Hu 1,  Dandan Chu 1,  Chen Hu 3,  Fei Liu 4,  Hengxiang Cui 5
Affiliations

Affiliations

  • 1 Department 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.
  • 2 Department of Cell Biology, School of Life Sciences, Nantong University, Nantong, China.
  • 3 Biomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology , Zibo, China.
  • 4 Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
  • 5 Shanghai 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.
  • # Contributed equally.
PMID: 40202498 DOI: 10.1083/jcb.202405142
Abstract

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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