NR AWQT
AU Xiang,W.; Windl,O.; Mitteregger,G.; Hummel,M.; Neumann,M.; Pace,C.; Lederer,R.M.; Mansmann,U.; Kretzschmar,H.A.
TI Gene expression alterations of the CNS in prion diseases
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Poster sessions PA-60
PT Konferenz-Poster
AB The pathogenesis of prion diseases in the central nervous system is so far insufficiently understood. In this study, we applied genome-wide gene expression technology to identify disease-associated alterations. To find common alterations in prion diseases, we studied post-mortem human brains with Creutzfeldt-Jakob disease (CJD) and scrapie-infected mouse brains. For the study on human brains, we collected frontal cortices from sporadic CJD patients and control individuals who had died of unrelated diseases, and analysed the gene expression using Affymetrix HGU 133A microarrays. For the expression profiling in mouse brains, we used C57/Bl6 female mice which were inoculated intracerebrally with 30 µl of a 10% brain homogenate of healthy mice or mice infected with mouseadapted scrapie (ME7 and RML) and studied the gene expression in mouse brains at different time points after inoculation using Affymetrix MOE430A microarrays. A comparison between human control and sCJD frontal cortices identified 79 upregulated and 275 downregulated genes, suggesting a pronounced reduction of gene expression activity in CJD cortex. In scrapie-infected mouse brains, we identified over 400 genes that showed changes in expression over the time course of infection and observed predominant upregulation of gene expression as compared to controls. Although upregulation of genes encoding immune response factors were observed both in CJD and scrapieinfected mouse brains, the range of the involved genes and the degree of the increased expression levels were more pronounced in scrapie-infected mouse brains. In CJD brains, downregulation of genes encoding synaptic proteins was more prominent. These findings support the hypothesis that immune response including activation of complement proteins and inflammatory factors is an important pathogenic event and precedes neuronal dysfunction. We further compared our findings in human CJD with data derived from scrapie mouse brains and identified a number of overlapping genes including upregulated genes such as Abca1, cathepsins, metallothioneins and downregulated gene like ADAM 23. These genes showed altered expression in brains of both human and mouse prion disease. The findings of this study shed light on the complex molecular events that occur during prion disease and offer a data resource for the biomarker selection.
AD W. Xiang, G. Mitteregger, M. Neumann, C. Pace, R.M. Lederer, H.A. Kretzschmar: Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Germany; O. Windl: Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Germany, and Veterinary Laboratories Agency, Weybridge, United Kingdom; M. Hummel, U. Mansmann: Department of Medical Informatics, Biometrics, and Epidemiology, Ludwig-Maximilians-University, Munich, Germany
SP englisch
PO Italien