期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 2, 期 52, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.3001059
关键词
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资金
- Michael J. Fox Foundation
- National Institute on Aging [K08AG024816]
- American Federation for Aging Research
- NIH [R01NS064155, R21NS060227, P01NS058793, R01NS049221, R24MH068855]
- M.E.M.O. Hoffman Foundation
- RJG Foundation
- Parkinson's Disease Foundation
- Parkinson's Disease Society of the UK
- Nationales Genomeforschungsnetz (Bundesministerium fur Bildung und Forschung) [01GS0115, TP9]
- Brain Net Europe II
- Arizona Alzheimer's Disease Core Center, Arizona Biomedical Research Commission, Prescott Family Initiative of the Michael J. Fox Foundation [P30AG19610]
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 gamma coactivator-1 alpha (PGC-1 alpha) are underexpressed in Parkinson's disease patients. Activation of PGC-1 alpha results in increased expression of nuclear-encoded subunits of the mitochondrial respiratory chain and blocks the dopaminergic neuron loss induced by mutant alpha-synuclein or the pesticide rotenone in cellular disease models. Our systems biology analysis of Parkinson's disease identifies PGC-1 alpha as a potential therapeutic target for early intervention.
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