TY - JOUR
T1 - PGC-1α promoter methylation in Parkinson's disease
AU - Su, Xiaomin
AU - Chu, Yaping
AU - Kordower, Jeffrey H.
AU - Li, Bin
AU - Cao, Hong
AU - Huang, Liang
AU - Nishida, Maki
AU - Song, Lei
AU - Wang, Difei
AU - Federoff, Howard J.
N1 - Publisher Copyright:
© 2015 Su et al.
PY - 2015/8/28
Y1 - 2015/8/28
N2 - 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-1 α 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-1 α 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-1 α promoter methylation in different cell types from the CNS. Indeed, in mouse primary cortical neurons, microglia and astrocytes, palmitate causes PGC-1 αgene promoter non-canonical cytosine methylation, reduced expression of the gene and reduced mitochondrial content. Moreover, intracerebroventricular (ICV) injection of palmitate to transgenic human a-synuclein mutant mice resulted in increased PGC-1 α promoter methylation, decreased PGC-1 α expression and reduced mitochondrial content in substantia nigra. Finally we provide evidence that dysregulation of ER stress and inflammatory signaling is associated with PGC-1 α promoter methylation. Together, these data strengthen the connection between saturated fatty acids, neuroflammation, ER stress, epigenetic alteration and bioenergetic compromise in PD.
AB - 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-1 α 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-1 α 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-1 α promoter methylation in different cell types from the CNS. Indeed, in mouse primary cortical neurons, microglia and astrocytes, palmitate causes PGC-1 αgene promoter non-canonical cytosine methylation, reduced expression of the gene and reduced mitochondrial content. Moreover, intracerebroventricular (ICV) injection of palmitate to transgenic human a-synuclein mutant mice resulted in increased PGC-1 α promoter methylation, decreased PGC-1 α expression and reduced mitochondrial content in substantia nigra. Finally we provide evidence that dysregulation of ER stress and inflammatory signaling is associated with PGC-1 α promoter methylation. Together, these data strengthen the connection between saturated fatty acids, neuroflammation, ER stress, epigenetic alteration and bioenergetic compromise in PD.
UR - http://www.scopus.com/inward/record.url?scp=84943339728&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84943339728&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0134087
DO - 10.1371/journal.pone.0134087
M3 - Article
C2 - 26317511
AN - SCOPUS:84943339728
SN - 1932-6203
VL - 10
JO - PloS one
JF - PloS one
IS - 8
M1 - e0134087
ER -