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.

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Background Adaptive behavioral prioritization requires flexible outputs from fixed neural circuits. In C. elegans, the prioritization of feeding vs. mate-searching depends on biological sex (males will abandon food to search for mates, while hermaphrodites will not) as well as developmental stage and feeding status. Previously, we found that males are less attracted than hermaphrodites to the food-associated odorant diacetyl, suggesting that sensory modulation may contribute to behavioral prioritization. Results We find that somatic sex acts cell-autonomously to reconfigure the olfactory circuit by regulating a key chemoreceptor, odr-10, in the AWA neurons. Moreover, we find that odr-10 has a significant role in food detection, the regulation of which contributes to sex differences in behavioral prioritization. Overexpression of odr-10 increases male food attraction and decreases off-food exploration; conversely, odr-10 loss impairs food taxis in both sexes. In larvae, both sexes prioritize feeding over exploration; correspondingly, the sexes have equal odr-10 expression and food attraction. Food deprivation, which transiently favors feeding over exploration in adult males, increases male food attraction by activating odr-10 expression. Furthermore, the weak expression of odr-10 in well-fed adult males has important adaptive value, allowing males to efficiently locate mates in a patchy food environment. Conclusions We find that modulated expression of a single chemoreceptor plays a key role in naturally occurring variation in the prioritization of feeding and exploration. The convergence of three independent regulatory inputs—somatic sex, age, and feeding status—on chemoreceptor expression highlights sensory function as a key source of plasticity in neural circuits.

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Primary cilia have essential roles in transducing signals in eukaryotes. At their core is the ciliary axoneme, a microtubule-based structure that defines cilium morphology and provides a substrate for intraflagellar transport. However, the extent to which axonemal microtubules are specialized for sensory cilium function is unknown. In the nematode Caenorhabditis elegans, primary cilia are present at the dendritic ends of most sensory neurons, where they provide a specialized environment for the transduction of particular stimuli. Here, we find that three tubulin isotypes-the a-tubulins TBA-6 and TBA-9 and the b-tubulin TBB-4-are specifically expressed in overlapping sets of C. elegans sensory neurons and localize to the sensory cilia of these cells. Although cilia still form in mutants lacking tba-6, tba-9, and tbb-4, ciliary function is often compromised: these mutants exhibit a variety of sensory deficits as well as the mislocalization of signaling components. In at least one case, that of the CEM cephalic sensory neurons, cilium architecture is disrupted in mutants lacking specific ciliary tubulins. While there is likely to be some functional redundancy among C. elegans tubulin genes, our results indicate that specific tubulins optimize the functional properties of C. elegans sensory cilia.

Parkinson's disease pathogenesis proceeds through several phases, culminating in the loss of dopaminergic neurons of the substantia nigra (SN). Although the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of oxidative SN injury is frequently used to study degeneration of dopaminergic neurons in mice and non-human primates, an understanding of the temporal sequence of molecular events from inhibition of mitochondrial complex 1 to neuronal cell death is limited. Here, microarray analysis and integrative data mining were used to uncover pathways implicated in the progression of changes in dopaminergic neurons after MPTP administration. This approach enabled the identification of small, yet consistently significant, changes in gene expression within the SN of MPTP-treated animals. Such an analysis disclosed dysregulation of genes in three main areas related to neuronal function: cytoskeletal stability and maintenance, synaptic integrity, and cell cycle and apoptosis. The discovery and validation of these alterations provide molecular evidence for an evolving cascade of injury, dysfunction, and cell death.

Highlights d In starved C. elegans males, DAF-16/FoxO activates the food chemoreceptor odr-10 d In well-fed males, sex-specific production of daf-7/TGF-b represses odr-10 d Chemosensory signals, not metabolic cues, activate daf-7 in males d The detection of food signals helps males tune the feedingexploration balance

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