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

Journal of pharmaceutical analysis, 2023-02, Vol.13 (2), p.187-200 [Peer Reviewed Journal]

2022 The Authors ;2022 The Authors. ;Copyright Xi'an Jiaotong University, Journal of Pharmaceutical Analysis Feb 2023 ;Copyright © Wanfang Data Co. Ltd. All Rights Reserved. ;2022 The Authors 2022 ;ISSN: 2095-1779 ;EISSN: 2214-0883 ;DOI: 10.1016/j.jpha.2022.11.006 ;PMID: 36908857

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Title:
PKM2-mediated neuronal hyperglycolysis enhances the risk of Parkinson's disease in diabetic rats
Author: Zhao, Ya ; Wang, Yanwei ; Wu, Yuying ; Tao, Cimin ; Xu, Rui ; Chen, Yong ; Qian, Linghui ; Xu, Tengfei ; Lian, Xiaoyuan
Subjects: 6-Hydroxydopamine ; Amphetamines ; Animal cognition ; Apoptosis ; Cell differentiation ; Cell fusion ; Cerebrospinal fluid ; Cognitive ability ; Diabetes ; Diabetes mellitus ; Dopamine receptors ; Drug dosages ; Epidemiology ; Glucose ; Glycolysis ; Homeostasis ; Hyperglycemia ; Hyperglycolysis ; Kinases ; Laboratory animals ; Metabolism ; Metabolites ; Metabolomics ; Mitochondria ; Mitochondrial fusion ; Movement disorders ; Nerve growth factor ; Neurodegeneration ; Neurodegenerative diseases ; Neuronal vulnerability ; Neurons ; Older people ; Original ; Parkinson's disease ; Pheochromocytoma cells ; PKM2 ; Pyruvate kinase ; Pyruvic acid ; Shikonin ; Tricarboxylic acid cycle ; Type 1 diabetes mellitus
Is Part Of: Journal of pharmaceutical analysis, 2023-02, Vol.13 (2), p.187-200
Description: 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. [Display omitted] •Increased risk of diabetic Parkinson's disease was related to high glucose of brain microenvironment.•PKM2 mediated high-glucose induced neuronal vulnerability to 6-OHDA•High glucose promoted abnormal mitochondrial fusion and apoptosis induced by 6-OHDA.•Inhibition of PKM2 blocked the development of diabetic Parkinson's disease.
Publisher: China: Elsevier B.V
Language: English
Identifier: ISSN: 2095-1779
EISSN: 2214-0883
DOI: 10.1016/j.jpha.2022.11.006
PMID: 36908857
Source: Open Access: DOAJ Directory of Open Access Journals
Open Access: PubMed Central
AUTh Library subscriptions: ProQuest Central

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

2022 The Authors ;2022 The Authors. ;Copyright Xi'an Jiaotong University, Journal of Pharmaceutical Analysis Feb 2023 ;Copyright © Wanfang Data Co. Ltd. All Rights Reserved. ;2022 The Authors 2022 ;ISSN: 2095-1779 ;EISSN: 2214-0883 ;DOI: 10.1016/j.jpha.2022.11.006 ;PMID: 36908857

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