Gene expression meta-analysis of Parkinson's disease and its relationship with Alzheimer's disease

Abstract

Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common neurodegenerative diseases and have been suggested to share common pathological and physiological links. Understanding the cross-talk between them could reveal potentials for the development of new strategies for early diagnosis and therapeutic intervention thus improving the quality of life of those affected. Here we have conducted a novel meta-analysis to identify differentially expressed genes (DEGs) in PD microarray datasets comprising 69 PD and 57 control brain samples which is the biggest cohort for such studies to date. Using identified DEGs, we performed pathway, upstream and protein-protein interaction analysis. We identified 1046 DEGs, of which a majority (739/1046) were downregulated in PD. YWHAZ and other genes coding 14-3-3 proteins are identified as important DEGs in signaling pathways and in protein-protein interaction networks (PPIN). Perturbed pathways also include mitochondrial dysfunction and oxidative stress. There was a significant overlap in DEGs between PD and AD, and over 99% of these were differentially expressed in the same up or down direction across the diseases. REST was identified as an upstream regulator in both diseases. Our study demonstrates that PD and AD share significant common DEGs and pathways, and identifies novel genes, pathways and upstream regulators which may be important targets for therapy in both diseases.

Keywords: Alzheimer’s disease; Gene expression; Meta-analysis; Parkinson’s disease; Systems analysis; Transcriptome analysis.

Fig. 1

Workflow of data processing. Outlier samples were removed, and data normalized before the detection (Present/Absent) call algorithm was used to remove data that was not reliably detected. For each study, probesets with absent calls across a chosen percentage of samples were removed. This was repeated in 5% intervals removing probesets with 5% up to 95% of samples absent. The percentage absent cut-off used was set to optimize the normal distribution of the data. After this, the bottom 5% of average expression values across samples was removed and meta-analysis performed

Fig. 2

Top 10 most significant pathways identified using the downregulated DEGs

Fig. 3

Protein-protein interaction subnetwork created using the first neighbour nodes of the 14–3-3 protein family in the DEG PPIN. Six 14–3-3 family genes, YWHAZ, YWHAB, YWHAG, YWHAE, YWHAQ and YWHAH, were in the top 10 hubs for the subnetwork created from the top 30 DEGs found in our PD meta-analysis. A subnetwork of these 14–3-3 family members and their first neighbours were created. There were 18 DEGs that mapped to this, with red nodes indicating upregulated genes and green nodes indicating downregulated genes. Blue nodes indicate 14–3-3 family members that are not PD DEGs. Octagons denote genes that were in the top 30 DEGs. This first neighbour network contains 139 nodes and 539 edges