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. 2008 Feb;9(1):1-13.
doi: 10.1007/s10048-007-0116-y. Epub 2008 Jan 12.

Towards a pathway definition of Parkinson's disease: a complex disorder with links to cancer, diabetes and inflammation

Linda B Moran  1 , Manuel B Graeber
Affiliations

Towards a pathway definition of Parkinson's disease: a complex disorder with links to cancer, diabetes and inflammation

Linda B Moran et al. Neurogenetics. 2008 Feb.

Abstract

We have previously established a first whole genome transcriptomic profile of sporadic Parkinson's disease (PD). After extensive brain tissue-based validation combined with cycles of iterative data analysis and by focusing on the most comparable cases of the cohort, we have refined our analysis and established a list of 892 highly dysregulated priority genes that are considered to form the core of the diseased Parkinsonian metabolic network. The substantia nigra pathways, now under scrutiny, contain more than 100 genes whose association with PD is known from the literature. Of those, more than 40 genes belong to the highly significantly dysregulated group identified in our dataset. Apart from the complete list of 892 priority genes, we present pathways revealing PD 'hub' as well as 'peripheral' network genes. The latter include Lewy body components or interact with known PD genes. Biological associations of PD with cancer, diabetes and inflammation are discussed and interactions of the priority genes with several drugs are provided. Our study illustrates the value of rigorous clinico-pathological correlation when analysing high-throughput data to make optimal use of the histopathological phenome, or morphonome which currently serves as the key diagnostic reference for most human diseases. The need for systematic human tissue banking, following the highest possible professional and ethical standard to enable sustainability, becomes evident.

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Figures

Fig. 1
Fig. 1
Dendrogram showing the results of unsupervised hierarchical clustering of the 1,145 probes encompassing the 892 priority genes (corresponding Affymetrix probe IDs and expression data are provided online in SI_Figure_1). The algorithm separates the control (left) from the Parkinson’s disease group (right) (rows: red, expression above average; black, average expression; green, below average). An explanation of sample designations, patient data and a quantitative colour code are also provided in SI_Figure_1
Fig. 2
Fig. 2
a Cell processes predicted to be influenced by the top up-regulated priority genes (164 genes showing a differential expression >1 log2) based on in silico analysis employing the ResNet database (PathwayStudio 5.0, Ariadne). P and expression values of all 1,145 probes can be found in SI_Table_1c. An online version of this figure with hyperlinks is provided as SI_Figure_3a. b The three disease conditions showing the strongest biological association with the group of top up-regulated priority genes which may serve as drivers of the disease process underlying PD. In silico analysis was performed employing the ResNet database of molecular interactions (Pathway-Studio 5.0, Ariadne). An online version of this figure with hyperlinks is provided as SI_Figure_3b
Fig. 3
Fig. 3
Hypothetical ‘super pathway’ not stratified for cell type illustrating known direct interactions between the 892 PD priority genes (regulation, expression and promoter binding only). A total of 417 interactions (relations) are shown and any unlinked entities were removed. Display style: by effect; cellular layout; colour codes: promoter binding, violet; green, positive regulation; red, negative regulation; grey and/or broken lines, unknown (Resnet 5.0 database, unedited). Blue shading around selected genes indicates their involvement in the cellular process and disease conditions depicted in Fig. 2a and b, respectively. Permutations of this figure with hyperlinks are provided online as SI_Figures_4a-c
Fig. 4
Fig. 4
Neuronal pathway containing proteins found in Lewy bodies [11]. Priority genes of this study are marked by the blue shading. An online version of this figure with hyperlinks and an overlay of expression values is provided as SI_Figure_6. Symmetrical layout, display by effect (PathwayStudio)
Fig. 5
Fig. 5
Interactions of known PD genes (marked yellow) with the priority genes of this study. Expression value overlay: red indicates up- regulation and blue indicates down-regulation in PD nigra. An online version of this figure with hyperlinks and an overlay of significance values is provided as SI_Figure_7. Cellular layout, display by effect (ResNet)
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