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.

Adult Conditional Knockout of PGC-1α Leads to Loss of Dopamine Neurons

“…Similar observations have recently been reported in adult conditional parkin knock-out mice and mice overexpressing PARIS due to the reduction of PGC-1α levels (Stevens et al, 2015). Together, these studies indicate that the maintenance of PGC-1α levels in PD could offer neuroprotective therapeutic opportunities in PD (Zheng et al, 2010; Clark et al, 2011; Shin et al, 2011; Eschbach et al, 2015; Su et al, 2015). …”

PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival

“…In conclusion, since the PARIS/PGC-1α cell death pathway appears to play a role in sporadic PD (Clark et al, 2011; Eschbach et al, 2015; Shin et al, 2011; Su et al, 2015; Zheng et al, 2010), therapeutic strategies aimed at inhibiting PARIS or maintaining PGC-1α function could be beneficial in both sporadic PD and PD due to mutations in parkin or PINK1 .…”

DNA methylation in Parkinson's disease

“…Recently, a new framework was proposed, linking free fatty acids and methylation status of the PGC‐1 α gene as an epigenetic contributor of sporadic PD: significant promoter‐proximal non‐canonical cytosine methylation of the PGC‐1 α gene was found in affected brain tissue from PD patients and it was shown that PGC‐1 α methylation was stimulated by the pro‐inflammatory fatty acid palmitate (Su et al . ).…”