Cellular and molecular life sciences : CMLSOct 11, 2011

Increasing and activating a key energy regulator helps protect dopamine neurons in a mouse model of Parkinson's disease

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Updated Apr 4, 2026

Abstract

Transgenic mice overexpressing PGC-1α in dopaminergic neurons show increased resistance to cell degeneration induced by the neurotoxin MPTP.

Elevated levels of mitochondrial antioxidants SOD2 and Trx2 were observed in the substantia nigra of transgenic mice.
PGC-1α overexpression provided protection against MPTP-induced loss of dopamine in the striatum.
Mitochondria from PGC-1α transgenic mice exhibited an increased respiratory control ratio compared to wild-type animals.
The small molecule compound resveratrol (RSV) activated PGC-1α and protected dopaminergic neurons against MPTP-induced cell degeneration.
In vitro studies indicated that RSV enhanced PGC-1α gene transcription and increased levels of SOD2 and Trx2 through the activation of SIRT1.

Simplified

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.

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Increasing and activating a key energy regulator helps protect dopamine neurons in a mouse model of Parkinson's disease

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