Cerebral gene expression profiles in sporadic Creutzfeldt-Jakob disease.

The pathomechanism of sporadic Creutzfeldt-Jakob disease (sCJD) in the central nervous system is insufficiently understood. The aims of this study were to identify differentially regulated genes in the frontal cortex of sCJD and to profile the gene expression patterns in sCJD by using Affymetrix HGU133A microarrays (Affymetrix, Santa Clara, CA). The microarray data were generated by dChip and analyzed by Significance Analysis of Microarray (SAM) software. A comparison between control and sCJD samples identified 79 upregulated and 275 downregulated genes, which showed at least 1.5- and 2-fold changes, respectively, in sCJD frontal cortex, with an estimated false discovery rate of 5% or less. The major alterations in sCJD brains included upregulation of the genes encoding immune and stress-response factors and elements involved in cell death and cell cycle, as well as prominent downregulation of genes encoding synaptic proteins. A comparison of the molecular subtypes of sCJD showed various expression patterns associated with particular subtypes. The range of the upregulated genes and the degree of the increased expression appeared to be correlated with the degree of the neuropathological alterations in particular subtypes. Conspicuously, sCJD brains showed a great similarity with ageing human brains, both in the global expression patterns and in the identified differentially expressed genes.

Identification of differentially expressed genes in scrapie-infected mouse brains by using global gene expression technology.

The pathogenesis of prion diseases, a class of transmissible fatal neurodegenerative diseases in humans and animals, is still unclear. The aim of this study was to identify the differentially regulated genes that correlate with the development of prion diseases for a better understanding of their pathological mechanisms. We employed Affymetrix Mouse Expression Arrays 430A containing >22,000 transcripts and compared the global gene expression profiles from brains of mice who were intracerebrally inoculated with scrapie strains ME7 and RML with those from brains of uninfected and mock-infected mice. The microarray data were analyzed by Significance Analysis of Microarrays, revealing 121 genes whose expression increased at least twofold in both ME7- and RML-infected mouse brains, with an estimated false discovery rate of < or =5%. These genes encode proteins involved in proteolysis, protease inhibition, cell growth and maintenance, the immune response, signal transduction, cell adhesion, and molecular metabolism. The time course of expression generally showed up-regulation of these genes from 120 days postinoculation (dpi) for ME7-inoculated mouse brains and from 90 dpi for RML-inoculated mouse brains. The onset of elevated expression correlated temporally with the onset of PrP(Sc) accumulation and the activation of glia, which may have contributed to neuronal cell death. Among the differentially regulated genes reported in the present study, the emergence of genes for several cathepsins and S100 calcium binding proteins was conspicuous. These and other genes reported here may represent novel potential diagnostic and therapeutic targets for prion disease.