Abstract
BackgroundPeroxisome proliferator-activated receptor-γ co-activator (PGC)-1α is a transcriptional co-activator of antioxidant genes and a master regulator of mitochondrial biogenesis. Parkinson's disease (PD) is associated with oxidative stress and mitochondrial dysfunction and recent work suggests a role for PGC-1α. We hypothesized that the rs8192678 PGC-1α single nucleotide polymorphism (SNP) may influence risk or age of onset of PD. The A10398G mitochondrial SNP has been inversely associated with risk of PD in some studies. In the current study we analyzed whether rs8192678 or other PGC-1α SNPs affect PD risk or age of onset, singularly or in association with the A10398G SNP.MethodsGenomic DNA samples from 378 PD patients and 173 age-matched controls were analyzed by multiplexed probe sequencing, followed by statistical analyses of the association of each SNP, alone or in combination, with risk or age of onset of PD. Adjustments were made for age of onset being less than the age of sampling, and for the observed dependence between these two ages. The PD samples were obtained as two separate cohorts, therefore statistical methods accounted for different sampling methods between the two cohorts, and data were analyzed using Cox regression adjusted for sampling in the risk set definition and in the model.ResultsThe rs8192678 PGC-1α SNP was not associated with the risk of PD. However, an association of the PGC-1α rs8192678 GG variant with longevity was seen in control subjects (p = 0.019). Exploratory studies indicated that the CC variant of rs6821591 was associated with risk of early onset PD (p = 0.029), with PD age of onset (p = 0.047), and with longevity (p = 0.022). The rs2970848 GG allele was associated with risk of late onset PD (p = 0.027).ConclusionsThese data reveal possible associations of the PGC-1α SNPs rs6821591 and rs2970848 with risk or age of onset of PD, and of the PGC-1α rs8192678 GG and the rs6821591 CC variants with longevity. If replicated in other datasets, these findings may have important implications regarding the role of PGC-1α in PD and longevity.
Highlights
Peroxisome proliferator-activated receptor-g co-activator (PGC)-1a is a transcriptional co-activator of antioxidant genes and a master regulator of mitochondrial biogenesis
PGC-1a is important for protection against MPTP toxicity [15] and levels of PGC-1a are reduced in substantia nigra neurons in Parkinson’s disease (PD) [20], suggesting a role for PGC-1a in the pathogenesis of PD
An initial analysis indicated a non-significant trend towards an association of the rs8192678 PGC-1a polymorphism with age of onset of PD
Summary
Peroxisome proliferator-activated receptor-g co-activator (PGC)-1a is a transcriptional co-activator of antioxidant genes and a master regulator of mitochondrial biogenesis. Parkinson’s disease (PD) is associated with oxidative stress and mitochondrial dysfunction and recent work suggests a role for PGC-1a. Mutations in a number of genes including a-synuclein (SNCA), Parkin, Leucine-Rich-Repeat-Kinase 2 (LRRK2), Phosphatase and Tensin (PTEN) Homolog-Induced Putative Kinase 1 (PINK1) and DJ-1 among others can cause PD or. These studies reveal that several genes that regulate mitochondrial function or oxidative stress influence the risk of PD [12,13,14]. PGC-1a is a multifunctional protein that activates most nuclear receptors and functions as a co-activator to many transcription factors with the net result of co-ordinately regulating mitochondrial biogenesis [16]. PGC-1a is important for protection against MPTP toxicity [15] and levels of PGC-1a are reduced in substantia nigra neurons in PD [20], suggesting a role for PGC-1a in the pathogenesis of PD
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