Transgenic expression and activation of PGC-1\u3b1 protect dopaminergic neurons in the MPTP mouse model of Parkinson's disease

Mitochondrial dysfunction and oxidative stress occur in Parkinson\u2019s disease (PD), but little is known about the molecular mechanisms controlling these events. Peroxisome proliferator-activated receptor-gamma coactivator-1\u3b1 (PGC-1\u3b1) is a transcriptional coactivator that is a master regulator of oxidative stress and mitochondrial metabolism. We show here that transgenic mice overexpressing PGC-1\u3b1 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-1\u3b1 overexpression also protected against MPTP-induced striatal loss of dopamine, and mitochondria from PGC-1\u3b1 transgenic mice showed an increased respiratory control ratio compared with wild-type animals. To modulate PGC-1\u3b1, 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\u3b1 overexpression. As studied in vitro, RSV activated PGC-1\u3b1 in dopaminergic SN4741 cells via the deacetylase SIRT1, and enhanced PGC-1\u3b1 gene transcription with increases in SOD2 and Trx2. Taken together, the results reveal an important function of PGC-1\u3b1 in dopaminergic neurons to combat oxidative stress and increase neuronal viability. RSV and other compounds acting via SIRT1/PGC-1\u3b1 may prove useful as neuroprotective agents in PD and possibly in other neurological disorders