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Comprehensive transcriptional profiling of prion infection in mouse models reveals networks of responsive genes.

ABSTRACT: Prion infection results in progressive neurodegeneration of the central nervous system invariably resulting in death. The pathological effects of prion diseases in the brain are morphologically well defined, such as gliosis, vacuolation, and the accumulation of disease-specific protease-resistant prion protein (PrPSc). However, the underlying molecular events that lead to the death of neurons are poorly characterised. In this study cDNA microarrays were used to profile gene expression changes in the brains of two different strains of mice infected with three strains of mouse-adapted scrapie. Extensive data was collected and analyzed, from which we identified a core group of 349 prion-related genes (PRGs) that consistently showed altered expression in mouse models. Gene ontology analysis assigned many of the up-regulated genes to functional groups associated with one of the primary neuropathological features of prion diseases, astrocytosis and gliosis; protein synthesis, inflammation, cell proliferation and lipid metabolism. Using a computational tool, Ingenuity Pathway Analysis (IPA), we were able to build networks of interacting genes from the PRG list. The regulatory cytokine TGFB1, involved in modulating the inflammatory response, was identified as the outstanding interaction partner for many of the PRGs. The majority of genes expressed in neurons were down-regulated; a number of these were involved in regulatory pathways including synapse function, calcium signalling, long-term potentiation and ERK/MAPK signalling. Two down-regulated genes coding for the transcription regulators, EGR1 and CREB1, were also identified as central to interacting networks of genes; these factors are often used as markers of neuronal activity and their deregulation could be key to loss of neuronal function. These data provides a comprehensive list of genes that are consistently differentially expressed in multiple scrapie infected mouse models. Building networks of interactions between these genes provides a means to understand the complex interplay in the brain during neurodegeneration. Resolving the key regulatory and signaling events that underlie prion pathogenesis will provide targets for the design of novel therapies and the elucidation of biomarkers. Keywords: disease state analysis

ORGANISM(S): Mus musculus

PROVIDER: GSE10310 | GEO | 2008/01/31

SECONDARY ACCESSION(S): PRJNA108535

REPOSITORIES: GEO

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Project description:Prion infection results in progressive neurodegeneration of the central nervous system invariably resulting in death. The pathological effects of prion diseases in the brain are morphologically well defined, such as gliosis, vacuolation, and the accumulation of disease-specific protease-resistant prion protein (PrPSc). However, the underlying molecular events that lead to the death of neurons are poorly characterised. In this study cDNA microarrays were used to profile gene expression changes in the brains of two different strains of mice infected with three strains of mouse-adapted scrapie. Extensive data was collected and analyzed, from which we identified a core group of 349 prion-related genes (PRGs) that consistently showed altered expression in mouse models. Gene ontology analysis assigned many of the up-regulated genes to functional groups associated with one of the primary neuropathological features of prion diseases, astrocytosis and gliosis; protein synthesis, inflammation, cell proliferation and lipid metabolism. Using a computational tool, Ingenuity Pathway Analysis (IPA), we were able to build networks of interacting genes from the PRG list. The regulatory cytokine TGFB1, involved in modulating the inflammatory response, was identified as the outstanding interaction partner for many of the PRGs. The majority of genes expressed in neurons were down-regulated; a number of these were involved in regulatory pathways including synapse function, calcium signalling, long-term potentiation and ERK/MAPK signalling. Two down-regulated genes coding for the transcription regulators, EGR1 and CREB1, were also identified as central to interacting networks of genes; these factors are often used as markers of neuronal activity and their deregulation could be key to loss of neuronal function. These data provides a comprehensive list of genes that are consistently differentially expressed in multiple scrapie infected mouse models. Building networks of interactions between these genes provides a means to understand the complex interplay in the brain during neurodegeneration. Resolving the key regulatory and signaling events that underlie prion pathogenesis will provide targets for the design of novel therapies and the elucidation of biomarkers. Keywords: disease state analysis C57BL/6 mice were inoculated by intracerebral infection of brain homogenate from mice clinically infected with the ME7, 79a and 22A strains of scrapie. In addition VM mice were also inoculated with the 22A scrapie strain. Mice were sacrificed at the onset of clinical diseases as manifested by uncoordinated gait, flaccid paralysis of the hind limbs, rigidity and abolishment of the righting reflex. Brain tissue was collected from these mice and the RNA isolated. Mouse CNS gene expression was analysed by two-colour microarray experiments using an in house manufactured 11K mouse cDNA microarray. RNA from individual infected mice was hybridized to each array versus pooled reference RNA from an equivalent number of age-matched, mock-infected control mice. In total we hybridized 34 different samples to microarrays in this experiment; 8-10 individual mice from each of the four sample groups were individually processed for separate microarrays. Hierachical clustering shows that the patterns of gene expression are for the most part common to the different mouse models . We used the program EDGE to identify genes that were differentially expressed in mouse brain during clinical disease. We used a P value cut-off of 0.05 as the criteria for selection of significantly differentially expressed genes. A similar design was used to determine gene expression profiles from C57BL/6 mice infected with a fourth strain of scrapie, RML. Total RNA from three mice, plus dye swaps, was hybridized to Agilent whole genome mouse arrays to validate genes identified using our manufactured BMAP arrays.

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Comprehensive transcriptional profiling of prion infection in mouse models reveals networks of responsive genes.

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