PKM2-mediated neuronal hyperglycolysis enhances the risk of Parkinson's disease in diabetic rats

Ya Zhao; Yanwei Wang; Yuying Wu; Cimin Tao; Rui Xu; Yong Chen; Linghui Qian; Tengfei Xu; Xiaoyuan Lian

doi:10.1016/j.jpha.2022.11.006

Volume 13 Issue 2

Mar. 2023

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Article Navigation > Journal of Pharmaceutical Analysis > 2023 > 13(2): 187-200

Ya Zhao, Yanwei Wang, Yuying Wu, Cimin Tao, Rui Xu, Yong Chen, Linghui Qian, Tengfei Xu, Xiaoyuan Lian. PKM2-mediated neuronal hyperglycolysis enhances the risk of Parkinson's disease in diabetic rats[J]. Journal of Pharmaceutical Analysis, 2023, 13(2): 187-200. doi: 10.1016/j.jpha.2022.11.006

Citation:

Ya Zhao, Yanwei Wang, Yuying Wu, Cimin Tao, Rui Xu, Yong Chen, Linghui Qian, Tengfei Xu, Xiaoyuan Lian. PKM2-mediated neuronal hyperglycolysis enhances the risk of Parkinson's disease in diabetic rats[J]. Journal of Pharmaceutical Analysis, 2023, 13(2): 187-200. doi: 10.1016/j.jpha.2022.11.006

Citation:

Ya Zhao, Yanwei Wang, Yuying Wu, Cimin Tao, Rui Xu, Yong Chen, Linghui Qian, Tengfei Xu, Xiaoyuan Lian. PKM2-mediated neuronal hyperglycolysis enhances the risk of Parkinson's disease in diabetic rats[J]. Journal of Pharmaceutical Analysis, 2023, 13(2): 187-200. doi: 10.1016/j.jpha.2022.11.006

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PKM2-mediated neuronal hyperglycolysis enhances the risk of Parkinson's disease in diabetic rats

doi: 10.1016/j.jpha.2022.11.006

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

Funds:

This work was supported by the National Natural Science Foundation of China (Grant Nos.: 82074039 and 82204584). We thank Beibei Wang of the Center of Cryo-Electron Microscopy (CCEM), Zhejiang University, for her technical assistance in Transmission Electron Microscopy. We appreciate the Core Facilities of Zhejiang University School of Medicine for providing facilities.

Received Date: Jun. 28, 2022
Accepted Date: Nov. 16, 2022
Rev Recd Date: Nov. 15, 2022
Publish Date: Mar. 07, 2023

Abstract

Abstract

Epidemiological and animal studies indicate that pre-existing diabetes increases the risk of Parkinson's disease (PD). However, the mechanisms underlying this association remain unclear. In the present study, we found that high glucose (HG) levels in the cerebrospinal fluid (CSF) of diabetic rats might enhance the effect of a subthreshold dose of the neurotoxin 6-hydroxydopamine (6-OHDA) on the development of motor disorders, and the damage to the nigrostriatal dopaminergic neuronal pathway. In vitro, HG promoted the 6-OHDA-induced apoptosis in PC12 cells differentiated to neurons with nerve growth factor (NGF) (NGF-PC12). Metabolomics showed that HG promoted hyperglycolysis in neurons and impaired tricarboxylic acid cycle (TCA cycle) activity, which was closely related to abnormal mitochondrial fusion, thus resulting in mitochondrial loss. Interestingly, HG-induced upregulation of pyruvate kinase M2 (PKM2) combined with 6-OHDA exposure not only mediated glycolysis but also promoted abnormal mitochondrial fusion by upregulating the expression of MFN2 in NGF-PC12 cells. In addition, we found that PKM2 knockdown rescued the abnormal mitochondrial fusion and cell apoptosis induced by HG+6-OHDA. Furthermore, we found that shikonin (SK), an inhibitor of PKM2, restored the mitochondrial number, promoted TCA cycle activity, reversed hyperglycolysis, enhanced the tolerance of cultured neurons to 6-OHDA, and reduced the risk of PD in diabetic rats. Overall, our results indicate that diabetes promotes hyperglycolysis and abnormal mitochondrial fusion in neurons through the upregulation of PKM2, leading to an increase in the vulnerability of dopaminergic neurons to 6-OHDA. Thus, the inhibition of PKM2 and restoration of mitochondrial metabolic homeostasis/pathways may prevent the occurrence and development of diabetic PD.
- Type 1 diabetes mellitus,
- Hyperglycolysis,
- Mitochondrial fusion,
- PKM2,
- Neuronal vulnerability,
- Parkinson's disease

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References(63)

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