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
  • 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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