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Int J Biol Sci 2015; 11(10):1140-1149. doi:10.7150/ijbs.12657

Research Paper

Activation of ER Stress and Autophagy Induced by TDP-43 A315T as Pathogenic Mechanism and the Corresponding Histological Changes in Skin as Potential Biomarker for ALS with the Mutation

Xuejing Wang1*, Shuang Zhou2*, Xuebing Ding1*, Mingming Ma3, Jiewen Zhang3, Yue Zhou4, Erxi Wu2✉, Junfang Teng1✉

1. Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
2. Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, 58105, USA
3. Department of Neurology, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China
4. Department of Statistics, North Dakota State University, Fargo, ND, 58105, USA
* Equal contribution

Abstract

TAR DNA binding protein 43 (TDP-43) A315T mutation (TDP-43A315T) has been found in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) as a disease causing mutation with enhanced protein aggregation, formation of protease-resistant fragments, and neurotoxicity. However, the molecular mechanisms for its pathogenic effects are largely unknown. In this study, we demonstrate that TDP-43A315T enhanced neuronal toxicity via activating endoplasmic reticulum (ER) stress-mediated apoptosis in SH-SY5Y cells. Moreover, autophagy was activated by overexpression of TDP-43A315T in a self-defensive manner to decrease neuronal toxicity. Inhibition of autophagy attenuates TDP-43A315T induced neuronal cell death. Furthermore, the expression levels of TDP-43, ER chaperone 78 kDa glucose-regulated protein (GRP-78), and autophagy marker microtubule-associated protein 1A/1B-light chain 3 (LC3) in the skin tissues from ALS patients with TDP-43A315T mutation were markedly higher than those from the healthy control. Thus, our findings provide new molecular evidence for TDP-43A315T neuropathology. In addition, the pathological change in the skin tissues of the patients with TDP-43A315T mutation can be used as a quick diagnostic biomarker.

Keywords: TDP-43A315T, Endoplasmic reticulum stress, Autophagy, Amyotrophic lateral sclerosis

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How to cite this article:
Wang X, Zhou S, Ding X, Ma M, Zhang J, Zhou Y, Wu E, Teng J. Activation of ER Stress and Autophagy Induced by TDP-43 A315T as Pathogenic Mechanism and the Corresponding Histological Changes in Skin as Potential Biomarker for ALS with the Mutation. Int J Biol Sci 2015; 11(10):1140-1149. doi:10.7150/ijbs.12657. Available from http://www.ijbs.com/v11p1140.htm