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

Hongxia Zhang; Chen Chen; Eric Erquan Zhang; Xiaotian Huang

doi:10.1016/j.isci.2024.109522

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

iScience. 2024 Mar 16;27(4):109522. doi: 10.1016/j.isci.2024.109522. eCollection 2024 Apr 19.

Authors

Hongxia Zhang^{1

2}, Chen Chen², Eric Erquan Zhang², Xiaotian Huang¹

Affiliations

¹ Department of Medical Microbiology, Jiangxi Medical College, Nanchang University, Nanchang 330006, China.
² National Institute of Biological Sciences, Beijing 102206, China.

Abstract

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.

Keywords: Cellular neuroscience; Molecular biology; Molecular neuroscience; Neuroscience.