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Liraglutide Regulates Mitochondrial Quality Control System Through PGC-1α in a Mouse Model of Parkinson’s Disease

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Abstract

Parkinson’s disease (PD) is a multifactorial disorder, and there is strong evidence that mitochondria play an essential role in the disorder. Factors that regulate the mechanism of the mitochondrial quality control system have been drawing more and more attention. PGC-1α (peroxisome proliferator-activated receptor-γ coactivator-1α) is a powerful transcription factor involved in regulation of mitochondrial function. Glucagon-like peptide 1 (GLP-1), a brain-gut peptide, can enter the central nervous system through the blood–brain barrier and play neuroprotective role. However, whether the GLP-1R agonist liraglutide regulates mitochondrial quality control system through PGC-1α is still unclear. We administered different doses of liraglutide to intervene MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD model, and then immunofluorescence, Western blot, and stereotactic injection of lentivirus to downregulate PGC-1α were used to explore the mechanisms underlying the protective effect of liraglutide in PD. The results showed that MPTP lead to decreased mitochondrial biogenesis, disrupted mitochondrial dynamics, inhibited mitochondrial autophagy, and promoted cell apoptosis. While liraglutide effectively attenuated the neurotoxicity of MPTP, including reversing the dyskinesia caused by MPTP and preserving the expression of GLP-1R, TH, and PGC-1α in the substantia nigra (SN), further experiments showed that downregulation of PGC-1α expression via stereotactic injection PGC-1α lentivirus into the SN reversed the liraglutide protective effects. By PGC-1α downregulation, we found that PGC-1α can not only regulate mitochondria biogenesis, mitochondria dynamics, and autophagy, but also regulate cell apoptosis. In summary, liraglutide has a neuroprotective effect in the PD model induced by MPTP. This protective effect is accomplished by activating PGC-1α, which regulates the mitochondrial quality control system.

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Data Availability

All the data and material from this study are available upon reasonable request through the corresponding author.

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Funding

This work was supported by grants from Science Foundation of Hebei Normal University under Grant Number L2020Z05, and Hebei Province Foundation for Returnees under Grant Number C20200341.

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Authors and Affiliations

  1. Department of Physiology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, 050024, People’s Republic of China

    Pengyue Wu, Yuxuan Dong, Bing Cao, Yanqiu Zhang, Yueyan Qi, Zhenlong Guan & Yanqin Wang

  2. Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, 050051, People’s Republic of China

    Jinhu Chen

  3. Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, 050051, People’s Republic of China

    Tianyuan Guan

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  1. Pengyue Wu
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  2. Yuxuan Dong
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Correspondence to Yanqin Wang.

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Wu, P., Dong, Y., Chen, J. et al. Liraglutide Regulates Mitochondrial Quality Control System Through PGC-1α in a Mouse Model of Parkinson’s Disease. Neurotox Res 40, 286–297 (2022). https://doi.org/10.1007/s12640-021-00460-9

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