TDP-43, a novel rhythmic protein, regulates the ubiquitination degradation of BMAL1, cellular glucose utilization and energy synthesis

In this study, we discovered that TDP-43 expression followed a rhythmic pattern, which was influenced by sleep deprivation. Knockdown of TDP-43 altered the mRNA and protein expression of multiple circadian genes, including BMAL1, CLOCK, CRY1, and PER2. Furthermore, TDP-43 knockdown affected the autonomous circadian wheel behavior, as well as the cognitive and balance abilities of mice. We also revealed that TDP-43 regulated the deubiquitination of BMAL1 by influencing the alternative splicing of USP13, thereby affecting the expression of USP13 and the ubiquitin-mediated degradation of BMAL1. Additionally, TDP-43 modulated the AMPK signaling pathway, leading to changes in cellular glucose uptake and ATP production. Overall design: M17 cells were infected with LentiCRISPR v2/TDP-43KO or control viruses, and synchronized for 36 hrs, and then collected with TRIzol reagent at CT12.