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

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.