Activation of PGC-1 protect dopaminergic neurons in the MPTP mouse model of Parkinson’s disease

Abstract

Peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) is a transcriptional coactivator that is a master regulator of oxidative stress and mitochondrial metabolism. Mitochondrial dysfunction and oxidative stress occur in Parkinson’s disease (PD), but little is known about the molecular mechanisms controlling these events. We report that transgenic mice overexpressing PGC-1 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. To modulate PGC-1, 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-1 overexpression. RSV also activated PGC-1 in dopaminergic SN4741 cells and enhanced PGC-1 gene transcription with increases in SOD2 and Trx2. Taken together the results reveal an important function of PGC-1 in dopaminergic neurons survival.