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lüll PGC-1alpha, a potential therapeutic target for early intervention in Parkinson s disease Zheng B; Liao Z; Locascio JJ; Lesniak KA; Roderick SS; Watt ML; Eklund AC; Zhang-James Y; Kim PD; Hauser MA; Grunblatt E; Moran LB; Mandel SA; Riederer P; Miller RM; Federoff HJ; Wullner U; Papapetropoulos S; Youdim MB; Cantuti-Castelvetri I; Young AB; Vance JM; Davis RL; Hedreen JC; Adler CH; Beach TG; Graeber MB; Middleton FA; Rochet JC; Scherzer CRSci Transl Med 2010[Oct]; 2 (52): 52ra73Parkinson'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-1alpha (PGC-1alpha) are underexpressed in Parkinson's disease patients. Activation of PGC-1alpha 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-1alpha as a potential therapeutic target for early intervention.|*Early Diagnosis[MESH]|*Genome-Wide Association Study[MESH]|*Heat-Shock Proteins/genetics/metabolism[MESH]|*Transcription Factors/genetics/metabolism[MESH]|Adult[MESH]|Aged[MESH]|Aged, 80 and over[MESH]|Computational Biology/methods[MESH]|Databases, Genetic[MESH]|Dopamine/metabolism[MESH]|Humans[MESH]|Male[MESH]|Middle Aged[MESH]|Neurons/metabolism/pathology[MESH]|Parkinson Disease/diagnosis/*genetics/pathology/*therapy[MESH]|Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha[MESH]|alpha-Synuclein/metabolism[MESH] |