Transgenic expression and activation of PGC-1α protect dopaminergic neurons in the MPTP mouse model of Parkinson’s disease
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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.
KeywordsPGC-1α RSV SIRT1 MPTP Dopaminergic neurons Parkinson’s disease
We thank M. Forsberg for help with the PGC transgenic mice, B. Spiegelmann for the PGC-1α promoter constructs, J. Son and E. Arenas for SN4741 cells, and E. Lehto for skillful technical assistance. This work was supported by the Academy of Finland, Sigrid Juselius Foundation, Finska Läkaresällskapet, Liv och Hälsa, The Finnish Parkinson Foundation, Magnus Ehrnrooth and Minerva Foundation, and Fondi di Ateneo at University of Palermo, VDL, MO and AB were supported by Ateneo of Palermo.
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