title: Pgc-1α overexpression downregulates Pitx3 and increases susceptibility to MPTP toxicity associated with decreased Bdnf.
abstract: Multiple mechanisms likely contribute to neuronal death in Parkinson's disease (PD), including mitochondrial dysfunction and oxidative stress. Peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC-1α) positively regulates the expression of genes required for mitochondrial biogenesis and the cell's antioxidant responses. Also, expression of PGC-1α-regulated genes is low in substantia nigra (SN) neurons in early PD. Thus upregulation of PGC-1α is a candidate neuroprotective strategy in PD. Here, an adeno-associated virus (AAV) was used to induce unilateral overexpression of Pgc-1α, or a control gene, in the SN of wild-type C57BL/6CR mice. Three weeks after AAV administration, mice were treated with saline or MPTP. Overexpression of Pgc-1α in the SN induced expression of target genes, but unexpectedly it also greatly reduced the expression of tyrosine hydroxylase (Th) and other markers of the dopaminergic phenotype with resultant severe loss of striatal dopamine. Reduced Th expression was associated with loss of Pitx3, a transcription factor that is critical for the development and maintenance of dopaminergic cells. Expression of the neurotrophic factor Bdnf, which also is regulated by Pitx3, similarly was reduced. Overexpression of Pgc-1α also led to increased sensitivity to MPTP-induced death of Th+ neurons. Pgc-1α overexpression alone, in the absence of MPTP treatment, did not lead to cell loss in the SN or to loss of dopaminergic terminals. These data demonstrate that overexpression of Pgc-1α results in dopamine depletion associated with lower levels of Pitx3 and enhances susceptibility to MPTP. These data may have ramifications for neuroprotective strategies targeting overexpression of PGC-1α in PD.
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. jclark3@bidmc.harvard.edu
authors.forename: Joanne
authors.initials: J
authors.lastname: Clark
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Silvaggi
authors.forename: Tomas
authors.initials: T
authors.lastname: Kiselak
authors.forename: Kangni
authors.initials: K
authors.lastname: Zheng
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Clore
authors.forename: Ying
authors.initials: Y
authors.lastname: Dai
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Bass
authors.forename: David K
authors.initials: DK
authors.lastname: Simon
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D000229:Dependovirus / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D020267:MPTP Poisoning / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018398:Homeodomain Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C433629:homeobox protein PITX3; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine