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

Enrico Glaab,Reinhard Schneider

doi:10.1016/j.nbd.2014.11.002

Abstract

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 NR4A2, a transcription factor 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 via downstream effects similar to disease-linked mutations and to expression changes in sporadic PD. Overall, the analyses suggest mechanistic explanations for the age-dependence of PD risk and reveal significant and robust shared process alterations with potential applications in biomarker development for pre-symptomatic risk assessment or early stage diagnosis.

Highlights

Parkinson's disease (PD) is one of the most common neurodegenerative disorders and a disease-modifying therapy is still not available
When determining the intersection between the differentially expressed transcripts/genes obtained from the PD meta-analysis with those from the aging data analysis, 120 significant transcripts (FDR b 0.05) mapping to unique shared genes were identified
20−40 years 40−60 years 60+ years transcripts/genes interest; (2) the implicit assumption of the clustering algorithm that a hierarchical structure exists among the samples is not fulfilled; and (3) the complexity and heterogeneity of the high-dimensional data prevents the unsupervised clustering approach

Summary

Introduction

Parkinson's disease (PD) is one of the most common neurodegenerative disorders and a disease-modifying therapy is still not available. With an average age of onset of 60 years and a risk of developing sporadic PD known to increase significantly with age, the disease has been linked with aging by several studies (Bender et al, 2006; Collier et al, 2011; Frey et al, 2004; Hindle, 2010; Levy, 2007; Kaasinen and Rinne, 2002; Naoi and Maruyama, 1999). Independent of the type and extent of association between aging and PD pathogenesis, various shared molecular hallmarks have been observed, including a gradual decline in dopamine synthesis (Scatton et al, 1983; Ota et al, 2006), reduced striatal density of the type 2 vesicular monoamine transporter (Frey et al, 2004) and increased levels of deleted mitochondrial.

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