TDP-43 deficiency in suprachiasmatic nucleus perturbs rhythmicity of neuroactivity in prefrontal cortex

Individuals within the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/ FTD) often experience disruptive mental behaviors and sleep -wake disturbances. The hallmark of ALS/ FTD is the pathological involvement of TAR DNA -binding protein 43 (TDP-43). Understanding the role of TDP-43 in the circadian clock holds promise for addressing these behavioral abnormalities. In this study, we unveil TDP-43 as a pivotal regulator of the circadian clock. TDP-43 knockdown induces intracellular arrhythmicity, disrupts transcriptional activation regulation, and diminishes clock genes expression. Moreover, our experiments in adult mouse reveal that TDP-43 knockdown, specifically within the suprachiasmatic nucleus (SCN), induces locomotor arrhythmia, arrhythmic c -Fos expression, and depression -like behavior. This observation offers valuable insights into the substantial impact of TDP-43 on the behavioral aberrations associated with ALS/FTD. In summary, our study illuminates the significance of TDP-43 in circadian regulation, shedding light on the circadian regulatory mechanisms that may elucidate the pathological underpinnings of ALS/FTD.