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

Bin Zheng, Zhixiang Liao, Joseph J. Locascio, Kristen A. Lesniak, Sarah S. Roderick, Marla L. Watt, Aron C. Eklund, Yanli Zhang-James, Peter D. Kim, Michael A. Hauser, Edna Grünblatt, Linda B. Moran, Silvia A. Mandel, Peter Riederer, Renee M. Miller, Howard J. Federoff, Ullrich Wüllner, Spyridon Papapetropoulos, Moussa B. Youdim, Ippolita Cantuti-CastelvetriAnne B. Young, Jeffery M. Vance, Richard L. Davis, John C. Hedreen, Charles H. Adler, Thomas G. Beach, Manuel B. Graeber, Frank A. Middleton, Jean Christophe Rochet, Clemens R. Scherzer

Research output: Contribution to journalArticle

465 Scopus citations

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.

Original languageEnglish (US)
Article number52ra73
JournalScience translational medicine
Volume2
Issue number52
DOIs
StatePublished - Oct 6 2010

ASJC Scopus subject areas

  • Medicine(all)

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    Zheng, B., Liao, Z., Locascio, J. J., Lesniak, K. A., Roderick, S. S., Watt, M. L., Eklund, A. C., Zhang-James, Y., Kim, P. D., Hauser, M. A., Grünblatt, E., Moran, L. B., Mandel, S. A., Riederer, P., Miller, R. M., Federoff, H. J., Wüllner, U., Papapetropoulos, S., Youdim, M. B., ... Scherzer, C. R. (2010). PGC-1α, a potential therapeutic target for early intervention in Parkinson's disease. Science translational medicine, 2(52), [52ra73]. https://doi.org/10.1126/scitranslmed.3001059