Transgenic expression and activation of PGC-1α protect dopaminergic neurons in the MPTP mouse model of Parkinson’s disease

Abstract

Mitochondrial dysfunction and oxidative stress occur in Parkinson's disease (PD), but little is known about the molecular mechanisms controlling these events. Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) is a transcriptional coactivator that is a master regulator of oxidative stress and mitochondrial metabolism. We show here that transgenic mice overexpressing PGC-1α in dopaminergic neurons are resistant against cell degeneration induced by the neurotoxin MPTP. The increase in neuronal viability was accompanied by elevated levels of mitochondrial antioxidants SOD2 and Trx2 in the substantia nigra of transgenic mice. PGC-1α overexpression also protected against MPTP-induced striatal loss of dopamine, and mitochondria from PGC-1α transgenic mice showed an increased respiratory control ratio compared with wild-type animals. To modulate PGC-1α, we employed the small molecular compound, resveratrol (RSV) that protected dopaminergic neurons against the MPTP-induced cell degeneration almost to the same extent as after PGC-1α overexpression. As studied in vitro, RSV activated PGC-1α in dopaminergic SN4741 cells via the deacetylase SIRT1, and enhanced PGC-1α gene transcription with increases in SOD2 and Trx2. Taken together, the results reveal an important function of PGC-1α in dopaminergic neurons to combat oxidative stress and increase neuronal viability. RSV and other compounds acting via SIRT1/PGC-1α may prove useful as neuroprotective agents in PD and possibly in other neurological disorders.

Effect of MPTP on mRNA expression of PGC-1α in mouse brain

“…PGC-1α is essential in normal mitochondrial functioning and its deficiency may contribute to neurodegeneration, while its stimulation demonstrated to be neuroprotective in certain models (Breidert et al, 2002;Dehmer et al, 2004;Eschbach et al, 2015;Mudo et al, 2012).…”

“…On the one hand, the transgenic overexpression of PGC-1α was proved to protective against MPTP (Mudo et al, 2012), on the other hand, the adenovirus vector-mediated overexpression of PGC-1α resulted in dopamine depletion in the SN (Ciron et al, 2012) and consequently enhanced susceptibility to MPTP (Clark et al, 2012). The clarification of this issue needs further studies.…”

Peroxisome proliferator‐activated receptor‐γ cofactors in neurodegeneration

“…This effect could be owing to excessive overexpression of PGC-1a, resulting in mitochondrial hyperactivity, anoxia, and increased production of ROS (39). This is in contrast with other studies, showing that transgenic overexpression of PGC-1a or activation of PGC-1a by resveratrol protects dopaminergic neurons in the MPTP mouse model of PD (41).…”

Parkinson';s Disease, Diabetes and Cognitive Impairment

“…The neuroprotective effect of PGC1-α was further demonstrated using transgenic mice overexpressing PGC-1α. This overexpression was found to attenuate the neurodegenerative effects of MPTP, with protection from the loss of dopaminergic neurons when compared to wild-type mice [37]. The same study also explored the effects of resveratrol (RSV), a compound that activates PGC-1α, on MPTP treated wildtype mice.…”

“…The same study also explored the effects of resveratrol (RSV), a compound that activates PGC-1α, on MPTP treated wildtype mice. They found that, while treatment with MPTP reduced the number of dopaminergic neurons in the substantia nigra by 44%, treatment with RSV increased the number of neurons to 83% that of the control group [37]. Analysis of gene sets involved in mitochondrial function and glucose metabolism showed that at least 10 gene sets were also associated with PD.…”