Comparative pathway and network analysis of brain transcriptome changes during adult aging and in Parkinson's disease

Aging is considered as one of the main factors promoting the risk for Parkinson's disease (PD) and common mechanisms of dopamine neuron degeneration in aging and PD have been proposed in recent years. Here, we use a statistical meta-analysis of human brain transcriptomics data to investigate potential mechanistic relationships between adult brain aging and PD pathogenesis at the pathway and network level. The analyses identify statistically significant shared pathway and network alterations in aging and PD and an enrichment in PD-associated sequence variants from genome-wide association studies among the jointly deregulated genes. We find robust discriminative patterns for groups of functionally related genes with potential applications as combined risk biomarkers to detect aging- and PD-linked oxidative stress, e.g. a consistent over-expression of metallothioneins matching with findings in previous independent studies. Interestingly, analyzing the regulatory network and mouse knockout expression data for the transcription factor NR4A2, previously associated with rare mutations in PD and here found as the most significantly under-expressed gene in PD among the jointly altered genes, suggests that aging-related NR4A2 expression changes may increase PD risk by producing downstream effects similar to disease-linked mutations and to expression changes observed in sporadic PD. Overall, the analyses suggest mechanistic explanations for the age-dependence of PD risk, reveal significant and robust shared process alterations in aging and PD, and examine their potential for biomarker applications in pre-symptomatic risk assessment or early-stage diagnosis.