PGC-1α promoter methylation in Parkinson's disease

Xiaomin Su, Yaping Chu, Jeffrey H. Kordower, Bin Li, Hong Cao, Liang Huang, Maki Nishida, Lei Song, Difei Wang, Howard J. Federoff

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

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-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.

Original languageEnglish (US)
Article numbere0134087
JournalPloS one
Volume10
Issue number8
DOIs
StatePublished - Aug 28 2015
Externally publishedYes

ASJC Scopus subject areas

  • General

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