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Int J Biol Sci 2015; 11(7):752-761. doi:10.7150/ijbs.11880

Research Paper

Valproate Attenuates 25-kDa C-Terminal Fragment of TDP-43-Induced Neuronal Toxicity via Suppressing Endoplasmic Reticulum Stress and Activating Autophagy

Xuejing Wang1*, Mingming Ma2*, Junfang Teng1, Xiangqian Che4, Wenwen Zhang1, Shuman Feng2, Shuang Zhou3, Ying Zhang3, Erxi Wu3✉, Xuebing Ding1✉

1. Department of neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
2. Department of neurology, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, China
3. Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, 58105, USA
4. Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University, Shanghai 200025, China
*Equal contribution

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease. To date, there is no any effective pharmacological treatment for improving patients' symptoms and quality of life. Rapidly emerging evidence suggests that C-terminal fragments (CTFs) of TAR DNA-binding protein of 43 kDa (TDP-43), including TDP-35 and TDP-25, may play an important role in ALS pathogenesis. Valproate (VPA), a widely used antiepileptic drug, has neuroprotective effects on neurodegenerative disorders. As for ALS, preclinical studies also provide encouraging evidence for multiple beneficial effects in ALS mouse models. However, the potential molecular mechanisms have not been explored. Here, we show protective effects of VPA against TDP-43 CTFs-mediated neuronal toxicity and its underlying mechanisms in vitro. Remarkably, TDP-43 CTFs induced neuronal damage via endoplastic reticulum (ER) stress-mediated apoptosis. Furthermore, autophagic self-defense system was activated to reduce TDP-43 CTFs-induced neuronal death. Finally, VPA attenuated TDP-25-induced neuronal toxicity via suppressing ER stress-mediated apoptosis and enhancing autophagy. Taken together, these results demonstrate that VPA exerts neuroprotective effects against TDP-43 CTFs-induced neuronal damage. Thus, we provide new molecular evidence for VPA treatment in patients with ALS and other TDP-43 proteinopathies.

Keywords: Amyotrophic lateral sclerosis, Valproate, 25 kDa C-terminal fragment of TDP-43, Endoplasmic reticulum stress, Autophagy

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) License. See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Wang X, Ma M, Teng J, Che X, Zhang W, Feng S, Zhou S, Zhang Y, Wu E, Ding X. Valproate Attenuates 25-kDa C-Terminal Fragment of TDP-43-Induced Neuronal Toxicity via Suppressing Endoplasmic Reticulum Stress and Activating Autophagy. Int J Biol Sci 2015; 11(7):752-761. doi:10.7150/ijbs.11880. Available from http://www.ijbs.com/v11p0752.htm