title: 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.
authors: Department of Experimental Biomedicine and Clinical Neuroscience, Division of Human Physiology, University of Palermo, Italy.
authors: Giuseppa
authors: G
authors: Mudò
authors: Johanna
authors: J
authors: Mäkelä
authors: Valentina
authors: V
authors: Di Liberto
authors: Timofey V
authors: TV
authors: Tselykh
authors: Melania
authors: M
authors: Olivieri
authors: Petteri
authors: P
authors: Piepponen
authors: Ove
authors: O
authors: Eriksson
authors: Annika
authors: A
authors: Mälkiä
authors: Alessandra
authors: A
authors: Bonomo
authors: Minna
authors: M
authors: Kairisalo
authors: Jose A
authors: JA
authors: Aguirre
authors: Laura
authors: L
authors: Korhonen
authors: Natale
authors: N
authors: Belluardo
authors: Dan
authors: D
authors: Lindholm
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine