PGC-1 α, A Potential Therapeutic Target for Early Intervention in Parkinson’s Disease

Abstract

Parkinson’s disease affects 5 million people worldwide, but the molecular mechanisms underlying its pathogenesis are still unclear. Here, we report a genome-wide meta-analysis of gene sets (groups of genes that encode the same biological pathway or process) in 410 samples from patients with symptomatic Parkinson’s and subclinical disease and healthy controls. We analyzed 6.8 million raw data points from nine genome-wide expression studies, and 185 laser-captured human dopaminergic neuron and substantia nigra transcriptomes, followed by two-stage replication on three platforms. We found 10 gene sets with previously unknown associations with Parkinson’s disease. These gene sets pinpoint defects in mitochondrial electron transport, glucose utilization, and glucose sensing and reveal that they occur early in disease pathogenesis. Genes controlling cellular bioenergetics that are expressed in response to peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α) are underexpressed in Parkinson’s disease patients. Activation of PGC-1α results in increased expression of nuclear-encoded subunits of the mitochondrial respiratory chain and blocks the dopaminergic neuron loss induced by mutant α-synuclein or the pesticide rotenone in cellular disease models. Our systems biology analysis of Parkinson’s disease identifies PGC-1α as a potential therapeutic target for early intervention.

Mitochondrial Biogenesis through Activation of Nuclear Signaling Proteins

“…Among them is PARIS, a zinc finger corepressor, which can suppress the transcriptional coactivator PGC1a . Consistent with this, PGC-1a responsive genes are underexpressed in microdissected dopaminergic neurons of Parkinson's disease mouse models, suggesting that this pathway could be causative in this disease (Beal 2009;Zheng et al 2010). Based on these data, it is possible to speculate that during mitophagy Parkin activation can signal to the nucleus through Paris degradation, resulting in an increase in PGC-1a and will subsequently promote mitochondrial biogenesis.…”

Identification of disease-distinct complex biomarker patterns by means of unsupervised machine-learning using an interactive R toolbox (Umatrix)

“…The latter processes are essentially regulated by bioactive lipids including ceramides, sphingolipids, lysophospholipids, eicosanoids, endocannabinoids, HETEs, omega-3 and omega-6 lipids and EETs [17,[51][52][53][54][55][56][57][58][59]. The relevance of subtle changes in complex regulatory circuits has been taken into account by modern omics-based analysis tools using "gene set enrichment analyses" for the detection of pattern changes [60,61]. Hence, the observation that a set of serum lipid markers contain information relevant for the separation of Parkinson patients from healthy subjects is biologically plausible.…”

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

“…Its ASN-induced [221] disturbances may be implicated in the pathogenesis of Parkinson's disease [40], and PGC-1α has been proposed as a therapeutic target in PD [239].…”