| First Author | Su X | Year | 2015 |
| Journal | PLoS One | Volume | 10 |
| Issue | 8 | Pages | e0134087 |
| PubMed ID | 26317511 | Mgi Jnum | J:243019 |
| Mgi Id | MGI:5907427 | Doi | 10.1371/journal.pone.0134087 |
| Citation | Su X, et al. (2015) PGC-1alpha Promoter Methylation in Parkinson's Disease. PLoS One 10(8):e0134087 |
| abstractText | 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 alpha (PGC-1alpha) 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-1alpha 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-1alpha 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-1alpha promoter methylation in different cell types from the CNS. Indeed, in mouse primary cortical neurons, microglia and astrocytes, palmitate causes PGC-1alpha gene promoter non-canonical cytosine methylation, reduced expression of the gene and reduced mitochondrial content. Moreover, intracerebroventricular (ICV) injection of palmitate to transgenic human alpha-synuclein mutant mice resulted in increased PGC-1alpha promoter methylation, decreased PGC-1alpha expression and reduced mitochondrial content in substantia nigra. Finally we provide evidence that dysregulation of ER stress and inflammatory signaling is associated with PGC-1alpha promoter methylation. Together, these data strengthen the connection between saturated fatty acids, neuroflammation, ER stress, epigenetic alteration and bioenergetic compromise in PD. |
