A Cross-Study Transcriptional Analysis of Parkinson's Disease

• Published in: PloS one Vol. 4; no. 3; p. e4955
• Main Authors: Sutherland, Greg T., Matigian, Nicholas A., Chalk, Alistair M., Anderson, Matthew J., Silburn, Peter A., Mackay-Sim, Alan, Wells, Christine A., Mellick, George D.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.03.2009; Public Library of Science (PLoS)
• Subjects: Acids; Alzheimer's disease; Analysis; Axon guidance; Brain; Brain architecture; Brain diseases; Brain research; Cell culture; Cell cycle; Datasets; Development and progression; Disease control; Disease susceptibility; Dopamine; Dopamine - metabolism; Dopamine receptors; Experiments; Gene expression; Gene Expression Profiling; Genes; Genetic aspects; Genetics and Genomics/Complex Traits; Genetics and Genomics/Gene Expression; Genomes; Humans; Insulin; Insulin-like growth factor I; Intercellular Signaling Peptides and Proteins - metabolism; Medical research; Microarray Analysis; Movement disorders; Neurodegenerative diseases; Neurological Disorders/Movement Disorders; Neurons; Neurons - metabolism; Neurons - pathology; Parkinson Disease - genetics; Parkinson's disease; Pathogenesis; Pathology/Neuropathology; Schizophrenia; Signal transduction; Signal Transduction - genetics; Stem cells; Studies; Substantia nigra; Tissues; Transcription; Transcription (Genetics); Transcription, Genetic; Queensland Australia; Australia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0004955

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.