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Overexpression of PGC-1α Influences Mitochondrial Signal Transduction of Dopaminergic Neurons

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Abstract

Parkinson’s disease (PD) is a common neurodegenerative disease in the elderly. Mitochondrial dysfunction plays an important role in the pathogenesis of PD. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a powerful transcription factor, interacting with multiple transcription factors and widely involving in the regulation of mitochondrial biogenesis, oxidative stress, and other processes. The present study investigated the neuroprotective effects and signal transduction mechanisms of the overexpression of PGC-1α on N-methyl-4-phenylpyridinium ion (MPP+)-induced mitochondrial damage in SH-SY5Y cell, establishing the cell model of overexpression of PGC-1α and the cell model of PD by using adenoviral vectors and MPP+. 3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide thiazolyl blue (MTT) assay was used to investigate the effects of MPP+ and adenovirus on the cell viability of SH-SY5Y cells and the cell viability of experimental groups. Western blot and real-time PCR analysis were used to detect the expression of PGC-1α. Flow cytometry and ELISA were used to detect mitochondrial membrane potential and the level of cytochrome C, respectively. The level of intracellular ATP and H2O2 was measured by multifunctional fluorescence microplate. Western blot analysis and real-time PCR were used to observe the expression of estrogen-related receptor α (ERRα), peroxisome proliferator-activated receptor γ (PPARγ), nuclear respiratory factor (NRF)-1, and NRF-2. Confocal fluorescence analysis was used to observe subcellular localization of PGC-1α in SH-SY5Y cells under the intervention of MPP+. The expression of PGC-1α messenger RNA and protein significantly increased in Adv-PGC-1α + GFP groups, compared with the control and Adv-GFP groups (P < 0.01). The overexpression of PGC-1α could increase mitochondrial membrane potential, reduce the release of mitochondrial cytochrome C, inhibit H2O2 production, and improve the level of ATP in SH-SY5Y cells. The trend of expression of ERRα, PPARγ, and NRF-1 was more consistent with PGC-1α, the most remarkable change is ERRα, but the expression of NRF-2 has no significant changes. Under the gradually increasing concentration of MPP+, microscale PGC-1α gradually appeared in the cytoplasm of SH-SY5Y cells. The overexpression of PGC-1α can inhibit MPP+-induced mitochondrial damage in SH-SY5Y cells, and PGC-1α may realize the neuroprotective effects via the ERRα, PPARγ, and NRF-1 pathway.

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Abbreviations

PGC-1α:

Peroxisome proliferator-activated receptor-γ coactivator-1α

MPP+ :

N-methyl-4-phenylpyridinium ion

NRF-1/2:

Nuclear respiratory factor 1/2

ERRα:

Estrogen-related receptor α

PPARγ:

Peroxisome proliferator-activated receptor γ

Cyt C:

Cytochrome C

TFAM:

Mitochondrial transcription factor A

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Acknowledgments

This work was supported by the National Natural Science Fund of China (General Program) “PGC-1α Signal transduction mechanism for the regulation of mitochondrial function Parkinson’s disease model” (No. 81271414).

Conflict of Interest

The authors declare that they have no competing interests.

Authors’ Contributions

Qinyong Ye conceived and supervised the study; Dongzhu Li, Wanling Huang, Yingqing Wang, and Chun Chen participated in the flow cytometry assay, ELISA, immunohistochemistry, Western blot analysis, real-time-PCR and helped to draft the manuscript; Erwang Si and Juhua Wang also helped to draft the manuscript; and Xiaochun Chen also conceived the study. All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Neurology, Fujian Institute of Geriatrics, The Affiliated Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian, 350001, China

    Qinyong Ye, Wanling Huang, Dongzhu Li, Erwang Si, Juhua Wang, Yingqing Wang, Chun Chen & Xiaochun Chen

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  1. Qinyong Ye
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Correspondence to Qinyong Ye.

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Ye, Q., Huang, W., Li, D. et al. Overexpression of PGC-1α Influences Mitochondrial Signal Transduction of Dopaminergic Neurons. Mol Neurobiol 53, 3756–3770 (2016). https://doi.org/10.1007/s12035-015-9299-7

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