Abstract
The study of Parkinson's disease (PD), like other complex neurodegenerative disorders, is limited by access to brain tissue from patients with a confirmed diagnosis. Alternatively the study of peripheral tissues may offer some insight into the molecular basis of disease susceptibility and progression, but this approach still relies on brain tissue to benchmark relevant molecular changes against. Several studies have reported whole-genome expression profiling in post-mortem brain but reported concordance between these analyses is lacking. Here we apply a standardised pathway analysis to seven independent case-control studies, and demonstrate increased concordance between data sets. Moreover data convergence increased when the analysis was limited to the five substantia nigra (SN) data sets; this highlighted the down regulation of dopamine receptor signaling and insulin-like growth factor 1 (IGF1) signaling pathways. We also show that case-control comparisons of affected post mortem brain tissue are more likely to reflect terminal cytoarchitectural differences rather than primary pathogenic mechanisms. The implementation of a correction factor for dopaminergic neuronal loss predictably resulted in the loss of significance of the dopamine signaling pathway while axon guidance pathways increased in significance. Interestingly the IGF1 signaling pathway was also over-represented when data from non-SN areas, unaffected or only terminally affected in PD, were considered. Our findings suggest that there is greater concordance in PD whole-genome expression profiling when standardised pathway membership rather than ranked gene list is used for comparison.
Highlights
Parkinson’s disease (PD, OMIM: #168600) is a uniquely human disease that is clinically characterised by cardinal motor symptoms such as postural instability, bradykinesia and resting tremor [1]
Microarrays promise much in elucidating the pathogenesis of complex diseases such as PD but the lack of concordance in IGF-1 Signaling VEGF Signaling Synaptic Long Term Potentiation Calcium Signaling ERK/MAPK Signaling PTEN Signaling JAK/Stat Signaling Ephrin Receptor Signaling Axonal Guidance Signaling
We have shown that a standardised approach to analysing PD-related microarray data can account for a considerable proportion of the discordance
Summary
Parkinson’s disease (PD, OMIM: #168600) is a uniquely human disease that is clinically characterised by cardinal motor symptoms such as postural instability, bradykinesia and resting tremor [1]. Several microarray-based studies have used human tissue to look for differentially expressed genes in Parkinson’s disease [12,13,14,15,16,17,18,19,20,21] The majority of these used post-mortem whole brain tissue from the substantia nigra (SN) [14,15,16,17] and most authors emphasised differential expression in the ubiquitin-proteasome system or cellular energy pathways, their published gene lists appeared quite discordant. Others extended their studies to include pathologically normal brain regions [12,18,20,21] and these highlighted other biological mechanisms such as G-Proteincoupled receptor signaling and transcriptional regulation
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