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Open AccessArticle

Insulin Resistance Promotes Parkinson’s Disease through Aberrant Expression of α-Synuclein, Mitochondrial Dysfunction, and Deregulation of the Polo-Like Kinase 2 Signaling

1
Department of Neurology, Taipei Medical University-Shuang Ho Hospital, New Taipei City 235, Taiwan
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Department of Neurology, College of Medicine, School of Medicine, Taipei Medical University, Taipei City 110, Taiwan
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Taipei Neuroscience Institute, Taipei Medical University, Taipei City 110, Taiwan
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College of Medical Science and Technology, Graduate Institute of Neural Regenerative Medicine, Taipei Medical University, Taipei City 110, Taiwan
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Department of Surgery, Taipei Medical University Hospital, Taipei City 110, Taiwan
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Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 110, Taiwan
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Taipei Cancer Center, Taipei Medical University, Taipei City 110, Taiwan
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Department of Hematology & Oncology, Taipei Medical University-Shuang Ho Hospital, New Taipei City 235, Taiwan
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Department of Clinical and Movement Neuroscience, Institute of Neurology, University College London, London WC1N 3BG, UK
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Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 235, Taiwan
*
Authors to whom correspondence should be addressed.
Cells 2020, 9(3), 740; https://doi.org/10.3390/cells9030740
Received: 30 January 2020 / Revised: 11 March 2020 / Accepted: 16 March 2020 / Published: 17 March 2020
(This article belongs to the Special Issue Neuroinflammation in Neurodegenerative and Neurological Diseases)
Background: Insulin resistance (IR), considered a hallmark of diabetes at the cellular level, is implicated in pre-diabetes, results in type 2 diabetes, and negatively affects mitochondrial function. Diabetes is increasingly associated with enhanced risk of developing Parkinson’s disease (PD); however, the underlying mechanism remains unclear. This study investigated the probable culpability of IR in the pathogenesis of PD. Methods: Using MitoPark mice in vivo models, diabetes was induced by a high-fat diet in the in vivo models, and IR was induced by protracted pulse-stimulation with 100 nM insulin treatment of neuronal cells, in vitro to determine the molecular mechanism(s) underlying altered cellular functions in PD, including mitochondrial dysfunction and α-synuclein (SNCA) aberrant expression. Findings: We observed increased SNCA expression in the dopaminergic (DA) neurons of both the wild-type and diabetic MitoPark mice, coupled with enhanced degeneration of DA neurons in the diabetic MitoPark mice. Ex vivo, in differentiated human DA neurons, IR was associated with increased SNCA and reactive oxygen species (ROS) levels, as well as mitochondrial depolarization. Moreover, we demonstrated concomitant hyperactivation of polo-like kinase-2 (PLK2), and upregulated p-SNCA (Ser129) and proteinase K-resistant SNCA proteins level in IR SH-SY5Y cells, however the inhibition of PLK2 reversed IR-related increases in phosphorylated and total SNCA. Similarly, the overexpression of peroxisome proliferator-activated receptor-γ coactivator 1-alpha (PGC)-1α suppressed ROS production, repressed PLK2 hyperactivity, and resulted in downregulation of total and Ser129-phosphorylated SNCA in the IR SH-SY5Y cells. Conclusions: These findings demonstrate that IR-associated diabetes promotes the development and progression of PD through PLK2-mediated mitochondrial dysfunction, upregulated ROS production, and enhanced SNCA signaling, suggesting the therapeutic targetability of PLK2 and/or SNCA as potential novel disease-modifying strategies in patients with PD. View Full-Text
Keywords: Parkinson’s disease; diabetes; insulin resistance; mitochondria; polo-like kinase 2; PLK2; α-synuclein; SNCA Parkinson’s disease; diabetes; insulin resistance; mitochondria; polo-like kinase 2; PLK2; α-synuclein; SNCA
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MDPI and ACS Style

Hong, C.-T.; Chen, K.-Y.; Wang, W.; Chiu, J.-Y.; Wu, D.; Chao, T.-Y.; Hu, C.-J.; Chau, K.-Y.D.; Bamodu, O.A. Insulin Resistance Promotes Parkinson’s Disease through Aberrant Expression of α-Synuclein, Mitochondrial Dysfunction, and Deregulation of the Polo-Like Kinase 2 Signaling. Cells 2020, 9, 740.

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