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Sci Transl Med. 2010 Oct 6;2(52):52ra73. doi: 10.1126/scitranslmed.3001059.

PGC-1α, a potential therapeutic target for early intervention in Parkinson's disease.

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  • 1Laboratory for Neurogenomics, Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, 65 Landsdowne Street, Suite 307A, Cambridge, MA 02139, USA.

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.

PMID:
20926834
[PubMed - indexed for MEDLINE]
PMCID:
PMC3129986
Free PMC Article

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