title: PGC-1α Promoter Methylation in Parkinson's Disease.
abstract: The etiopathogenesis of sporadic Parkinson's disease (PD) remains elusive although mitochondrial dysfunction has long been implicated. Recent evidence revealed reduced expression of peroxisome proliferator-activated receptor gamma coactivator-1 α (PGC-1α) and downstream regulated nuclear encoded respiratory complex genes in affected brain tissue from PD patients. We sought to determine whether epigenetic modification of the PGC-1α gene could account for diminished expression. In substantia nigra from PD patients but not control subjects, we show significant promoter-proximal non-canonical cytosine methylation of the PGC-1α gene but not an adjacent gene. As neuroinflammation is a prominent feature of PD and a mediator of epigenetic change, we evaluated whether the pro-inflammatory fatty acid, palmitate, would stimulate PGC-1α promoter methylation in different cell types from the CNS. Indeed, in mouse primary cortical neurons, microglia and astrocytes, palmitate causes PGC-1α gene promoter non-canonical cytosine methylation, reduced expression of the gene and reduced mitochondrial content. Moreover, intracerebroventricular (ICV) injection of palmitate to transgenic human α-synuclein mutant mice resulted in increased PGC-1α promoter methylation, decreased PGC-1α expression and reduced mitochondrial content in substantia nigra. Finally we provide evidence that dysregulation of ER stress and inflammatory signaling is associated with PGC-1α promoter methylation. Together, these data strengthen the connection between saturated fatty acids, neuroflammation, ER stress, epigenetic alteration and bioenergetic compromise in PD.
authors: Department of Neuroscience, Georgetown University Medical Center, Washington DC, United States of America.
authors: Xiaomin
authors: X
authors: Su
authors: Department of Neurological Science, Rush University Medical Center, Chicago, Illinois, United States of America.
authors: Yaping
authors: Y
authors: Chu
authors: Department of Neurological Science, Rush University Medical Center, Chicago, Illinois, United States of America.
authors: Jeffrey H
authors: JH
authors: Kordower
authors: Department of Neuroscience, Georgetown University Medical Center, Washington DC, United States of America.
authors: Bin
authors: B
authors: Li
authors: Department of Neuroscience, Georgetown University Medical Center, Washington DC, United States of America.
authors: Hong
authors: H
authors: Cao
authors: Department of Neuroscience, Georgetown University Medical Center, Washington DC, United States of America.
authors: Liang
authors: L
authors: Huang
authors: Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington DC, United States of America.
authors: Maki
authors: M
authors: Nishida
authors: Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington DC, United States of America.
authors: Lei
authors: L
authors: Song
authors: Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington DC, United States of America.
authors: Difei
authors: D
authors: Wang
authors: Department of Neuroscience, Georgetown University Medical Center, Washington DC, United States of America; Department of Neurology, Georgetown University Medical Center, Washington DC, United States of America.
authors: Howard J
authors: HJ
authors: Federoff
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D019175:DNA Methylation / Q000187:drug effects; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D019308:Palmitic Acid / Q000008:administration & dosage / Q000494:pharmacology; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic / Q000187:drug effects; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D019308:Palmitic Acid