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Thioredoxin-Interacting Protein (TXNIP) Regulates Parkin/PINK1-mediated Mitophagy in Dopaminergic Neurons Under High-glucose Conditions: Implications for Molecular Links Between Parkinson’s Disease and Diabetes

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Abstract

Patients with diabetes mellitus have a higher risk of developing Parkinson’s disease (PD). However, the molecular links between PD and diabetes remain unclear. In this study, we investigated the roles of thioredoxin-interacting protein (TXNIP) in Parkin/PINK1-mediated mitophagy in dopaminergic (DA) cells under high-glucose (HG) conditions. In streptozotocin-induced diabetic mice, TXNIP was upregulated and autophagy was inhibited in the midbrain, while the loss of DA neurons was accelerated by hyperglycemia. In cultured PC12 cells under HG, TXNIP expression was upregulated and the intracellular reactive oxygen species (ROS) levels increased, leading to cell death. Autophagic flux was further blocked and PINK1 expression was decreased under HG conditions. Parkin expression in the mitochondrial fraction and carbonyl cyanide 3-chlorophenylhydrazone (CCCP)-induced co-localization of COX IV (marker for mitochondria) and LAMP1 (marker for lysosomes) were also significantly decreased by HG. Overexpression of TXNIP was sufficient to decrease the expression of both PINK1 and Parkin in PC12 cells, while knockdown of the expression of TXNIP by siRNA decreased intracellular ROS and attenuated cellular injury under HG. Moreover, inhibition of TXNIP improved the CCCP-induced co-localization of COX IV and LAMP1 in PC12 cells under HG. Together, these results suggest that TXNIP regulates Parkin/PINK1-mediated mitophagy under HG conditions, and targeting TXNIP may be a promising therapeutic strategy for reducing the risk of PD under hyperglycemic conditions.

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Acknowledgements

This work was supported by the National Science Foundation of China (81601098 and 81603181), the Natural Science Foundation of Jiangsu Province (BK20150302, BK20170004), the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (19KJB310016), Suzhou Science and Technology for People’s Livelihood (SYS201706), and the Natural Science Foundation of Suzhou (SYSD2018099).

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  1. Cun-Jin Su and Zhu Shen have contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China

    Cun-Jin Su, Zhu Shen, De-Lai Xu, Feng-Lun Zhao, Jie Pan & Ai-Ming Shi

  2. Institute of Neuroscience, Soochow University, Suzhou, 215004, China

    Cun-Jin Su, Ru-Xiao Cui, Ya Huang & Tong Liu

  3. Department of Clinical Pharmacology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China

    Yun-Li Yu

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  1. Cun-Jin Su
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Su, CJ., Shen, Z., Cui, RX. et al. Thioredoxin-Interacting Protein (TXNIP) Regulates Parkin/PINK1-mediated Mitophagy in Dopaminergic Neurons Under High-glucose Conditions: Implications for Molecular Links Between Parkinson’s Disease and Diabetes. Neurosci. Bull. 36, 346–358 (2020). https://doi.org/10.1007/s12264-019-00459-5

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