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Diallyl Trisulfide Protects Motor Neurons from the Neurotoxic Protein TDP-43 via Activating Lysosomal Degradation and the Antioxidant Response

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Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive motor neuron disease for which only limited effective therapeutics are available. Currently, TAR DNA-binding protein 43 (TDP-43) is recognized as a pathological and biochemical marker for ALS. Increases in the levels of aggregated or mislocalized forms of TDP-43 might result in ALS pathology. Therefore, clearance pathways for intracellular protein aggregates have been suggested as potential therapeutic targets for the treatment of ALS. Here we report that treatment of motor neuron-like NSC34 cells overexpressing TDP-43 with diallyl trisulfide (DATS) induced neuronal autophagy and lysosomal clearance of TDP-43 and C-terminal TDP-43 fragments. We also observed that the antioxidant transcription factor NF-E2-related factor 2 (Nrf2) was accumulated in the nucleus and the expression of the antioxidant enzymes heme oxygenase1 (HO-1) and NAD(P)H:quinone oxidoreductase (NQO1) was increased. Consequently, DATS suppressed the increase in the levels of reactive oxygen species induced by TDP-43 expression. This study extends the findings of prior reports indicating that lower doses of DATS mediate cell survival in part by inducing autophagy and activating the Nrf2/antioxidant response element pathway.

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Acknowledgements

We thank Dr. Rugao Liu at University of Louisville, USA for the kind gift of the NSC-34 cell line. We thank Dr. Jemeen Sreedharan and Dr. Christopher E. Shaw for kind gifts of the two mutants plamids, Dr. Guanghui Wang for EGFP-TDP-25 plasmid and Dr. Leonard Petrucelli GFP-TDP-35 plasmid. We thank Yushan Zhu for his technical support. This study was supported in part by grants from the National Natural Science Foundation of China (Nos. 30900460 and 81171210) and by the Hebei Science and Technology Department (No. 11966122D). We also would like to thank Editage [http://www.editage.cn] for English language editing.

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Authors and Affiliations

  1. Department of Neurology, Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, 050000, Hebei, China

    Chang Liu, Yi Li, Hong Jiang, Weisong Duan, Yansu Guo, Chunyan Li & Kun Hong

  2. Institute of Cardiocerebrovascular Disease, Shijiazhuang, 050000, Hebei, China

    Chang Liu, Yi Li, Hong Jiang, Weisong Duan, Yansu Guo, Chunyan Li & Kun Hong

  3. Neurological Laboratory of Hebei Province, Shijiazhuang, 050000, Hebei, China

    Chang Liu, Yi Li, Hong Jiang, Weisong Duan, Yansu Guo, Chunyan Li & Kun Hong

  4. Department of Neurology, Rizhao Central Hospital, Rizhao, 276800, Shandong, China

    Bingquan Leng

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  1. Chang Liu
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Liu, C., Leng, B., Li, Y. et al. Diallyl Trisulfide Protects Motor Neurons from the Neurotoxic Protein TDP-43 via Activating Lysosomal Degradation and the Antioxidant Response. Neurochem Res 43, 2304–2312 (2018). https://doi.org/10.1007/s11064-018-2651-3

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