Research Paper Volume 11, Issue 20 pp 8937—8950
Beneficial effects of PGC-1α in the substantia nigra of a mouse model of MPTP-induced dopaminergic neurotoxicity
- 1 Department of Neurology, Fujian Institute of Geriatrics, The Affiliated Union Hospital of Fujian Medical University, Fuzhou, Fujian, China
- 2 Clinical Medicine, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- 3 Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China
Received: November 12, 2018 Accepted: October 5, 2019 Published: October 21, 2019
https://doi.org/10.18632/aging.102357How to Cite
Copyright © 2019 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Background: Mitochondrial dysfunction and oxidative stress are closely associated with the pathogenesis of Parkinson’s disease. Peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC-1α) is thought to play multiple roles in the regulation of mitochondrial biogenesis and cellular energy metabolism. We recently reported that altering PGC-1α gene expression modulates mitochondrial functions in N-methyl-4-phenylpyridinium ion (MPP+) treated human SH-SY5Y neuroblastoma cells, possibly via the regulation of Estrogen-related receptor α (ERRα), nuclear respiratory factor 1 (NRF-1), nuclear respiratory factor 2 (NRF-2) and peroxisome proliferator-activated receptor γ (PPARγ) expression. In the present study, we aimed to further investigate the potential beneficial effects of PGC-1α in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated C57BL mice.
Methods: The overexpression or knockdown of the PGC-1α gene in the mouse model of dopaminergic neurotoxicity was performed using a stereotactic injection of lentivirus in MPTP-treated male C57BL/6 mice. Mice were randomly assigned to one of 6 groups (n=24 per group): normal saline (NS) intraperitoneal injection (i.p.) (con); MPTP i.p. (M); solvent of the lentivirus striatal injection (lentivirus control) + MPTP i.p. (LVcon+M); lentivirus striatal injection + MPTP i.p. (LV+M); LV-PGC-1α striatum injection + MPTP i.p. (LVPGC+M); and LV-PGC-1α-siRNA striatal injection + MPTP i.p. (LVsiRNA+M). Intraperitoneal injections of MPTP/NS were conducted two weeks after lentivirus injection.
Results: We found significant improvement in motor behavior and increases in tyrosine hydroxylase expression in the substantia nigra (SN) in the brains of mice in the LVPGC+M group. The opposite tendency was observed in those in the LVsiRNA+M group. The expression of superoxide dismutase (SOD) in the SN region was also consistent with the changes in PGC-1α expression. Electron microscopy showed an increasing trend in the mitochondrial density in the LVPGC+M group and a decreasing trend in the M and LVsiRNA+M groups compared to that in the controls.
Conclusions: Our results indicated that PGC-1α rescues the effects of MPTP-induced mitochondrial dysfunction in C57BL mice.
Abbreviations
PGC-1α: Peroxisome proliferator-activated receptor-γ; coactivator-1α: MPTP1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; SOD: Superoxide Dismutase; TH: Tyrosine Hydroxylase; SN: Substantia Nigra; LV: Lentivirus.