DJ-1 Suppresses Cytoplasmic TDP-43 Aggregation in Oxidative Stress-Induced Cell Injury

Article type: Research Article

Authors: Lei, Yang^{a; 1} | Zhang, Zhi-Feng^{a; b; 1} | Lei, Rui-Xue^a | Wang, Shu^a | Zhuang, Yang^a | Liu, An-Chun^a | Wu, Yan^a | Chen, Juan^a | Tang, Jun-Chun^a | Pan, Meng-Xian^a | Liu, Rui^a | Liao, Wei-Jing^c | Feng, Yu-Gong^d | Wan, Qi^{d; *} | Zheng, Mei^{e; *}

Affiliations: [a] Department of Physiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences, Wuhan University School of Medicine, Wuhan, China | [b] Department of Physiology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei, China | [c] Center for Brain Clinic, Zhongnan Hospital, Wuhan University School of Medicine, Wuhan, China | [d] Research Institute of Neuroregeneration & Neurorehabilitation, and Department of Neurosurgery, Qingdao University, Qingdao, China | [e] Department of Neurology, Beijing University Third Hospital, Beijing, China

Correspondence: [*] Correspondence to: Qi Wan, Research Institute of Neuroregeneration & Neurorehabilitation, and Department of Neurosurgery, Qingdao University, 308 Ningxia Street, Qingdao 266071, China. E-mail: qwanwh@hotmail.com and Mei Zheng, Department of Neurology, Beijing University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, China. E-mail: zhengm0420@sina.com.

Note: [1] These authors contributed equally to this work.

Abstract: DJ-1 (also called PARK7) is a multifunctional redox-sensitive protein that is protective against oxidative stress-induced cell death. TAR DNA-binding protein 43 (TDP-43) is a major protein component of pathological inclusions in amyotrophic lateral sclerosis and frontotemporal dementia. Reducing aberrant aggregation of TDP-43 is a potential approach to prevent cell death. To investigate whether DJ-1 might inhibit TDP-43 aggregation to exert a protective effect in oxidative stress-induced injury, we tested the protein level and subcellular localization of TDP-43 and DJ-1 in SH-SY5Y cells transfected with wild-type DJ-1, DJ-1 mutant (L166P) cDNA, or DJ-1 siRNA. We show that oxidative stress induced by paraquat leads to the formation of cytosolic TDP-43 aggregation in SH-SY5Y cells. DJ-1 overexpression decreases paraquat-induced cytoplasmic accumulation of TDP-43 in SH-SY5Y cells and protects against paraquat-induced cell death. Transfection of DJ-1 L166P mutant or DJ-1 siRNA leads to increased cytosolic aggregation of TDP-43 in paraquat-treated SH-SY5Y cells and promotes cell death. These data suggest that DJ-1 may protect against oxidative stress-induced cell death through the suppression of cytoplasmic TDP-43 aggregation.

Keywords: Amyotrophic lateral sclerosis, oxidative stress, PARK7, TAR DNA-binding protein 43

DOI: 10.3233/JAD-180460

Journal: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1001-1014, 2018