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Realgar-Induced Neurotoxicity: Crosstalk Between the Autophagic Flux and the p62-NRF2 Feedback Loop Mediates p62 Accumulation to Promote Apoptosis

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Abstract

Realgar is a traditional Chinese medicine that contains arsenic. It has been reported that the abuse of medicine-containing realgar has potential central nervous system (CNS) toxicity, but the toxicity mechanism has not been elucidated. In this study, we established an in vivo realgar exposure model and selected the end product of realgar metabolism, DMA, to treat SH-SY5Y cells in vitro. Many assays, including behavioral, analytical chemistry, and molecular biology, were used to elucidate the roles of the autophagic flux and the p62-NRF2 feedback loop in realgar-induced neurotoxicity. The results showed that arsenic could accumulate in the brain, causing cognitive impairment and anxiety-like behavior. Realgar impairs the ultrastructure of neurons, promotes apoptosis, perturbs autophagic flux homeostasis, amplifies the p62-NRF2 feedback loop, and leads to p62 accumulation. Further analysis showed that realgar promotes the formation of the Beclin1-Vps34 complex by activating JNK/c-Jun to induce autophagy and recruit p62. Meanwhile, realgar inhibits the activities of CTSB and CTSD and changes the acidity of lysosomes, leading to the inhibition of p62 degradation and p62 accumulation. Moreover, the amplified p62-NRF2 feedback loop is involved in the accumulation of p62. Its accumulation promotes neuronal apoptosis by upregulating the expression levels of Bax and cleaved caspase-9, resulting in neurotoxicity. Taken together, these data suggest that realgar can perturb the crosstalk between the autophagic flux and the p62-NRF2 feedback loop to mediate p62 accumulation, promote apoptosis, and induce neurotoxicity.

Graphical Abstract

Realgar promotes p62 accumulation to produce neurotoxicity by perturbing the autophagic flux and p62-NRF2 feedback loop crosstalk

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Funding

These authors acknowledge the funding support received from the National Natural Science Foundation of China (grant number 81873082) and the National College Student Innovation and Entrepreneurship Training Program in China (grant number 202010159013).

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Authors and Affiliations

  1. Department of Health Laboratory Technology, School of Public Health, China Medical University, Shengyang, 110122, China

    Rui Feng, Jieyu Liu, Zhao Yang, Tiantian Yao, Ping Ye, Xiuhan Li, Jiaxin Zhang & Hong Jiang

  2. Key Laboratory of Liaoning Province On Toxic and Biological Effects of Arsenic, Shengyang, 110122, China

    Hong Jiang

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Contributions

All authors contributed to the study conception and design. The material preparation, data collection and analysis were performed by Rui Feng, Jieyu Liu, and Zhao Yang. The first draft of the manuscript was written by Rui Feng, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Feng, R., Liu, J., Yang, Z. et al. Realgar-Induced Neurotoxicity: Crosstalk Between the Autophagic Flux and the p62-NRF2 Feedback Loop Mediates p62 Accumulation to Promote Apoptosis. Mol Neurobiol 60, 6001–6017 (2023). https://doi.org/10.1007/s12035-023-03452-2

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