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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

  • Cun-Jin Su
  • Zhu Shen
  • Ru-Xiao Cui
  • Ya Huang
  • De-Lai Xu
  • Feng-Lun Zhao
  • Jie Pan
  • Ai-Ming Shi
  • Tong LiuEmail author
  • Yun-Li YuEmail author
Original Article

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.

Keywords

Diabetes mellitus Parkinson’s disease High glucose TXNIP Mitophagy PC12 cells 

Notes

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).

Conflict of interest

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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Copyright information

© Shanghai Institutes for Biological Sciences, CAS 2020

Authors and Affiliations

  1. 1.Department of PharmacyThe Second Affiliated Hospital of Soochow UniversitySuzhouChina
  2. 2.Institute of NeuroscienceSoochow UniversitySuzhouChina
  3. 3.Department of Clinical PharmacologyThe Second Affiliated Hospital of Soochow UniversitySuzhouChina

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