Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of mouse scrapie ME7-infected and mock-infected brains at two important preclinical time points and at terminal stages

ABSTRACT: The experiment describes the dynamic transcriptional alterations in brains of ME7- infected, and age-matched, mock-inoculated mice immediatly before inoculation, at two important preclinical time points and at terminal stages.

ORGANISM(S): Mus musculus

SUBMITTER: Manuela Hummel

PROVIDER: E-MEXP-1005 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Transcriptome analysis reveals altered cholesterol metabolism during the neurodegeneration in mouse scrapie model.

Xiang Wei W Hummel Manuela M Mitteregger Gerda G Pace Claudia C Windl Otto O Mansmann Ulrich U Kretzschmar Hans A HA

Journal of neurochemistry 20070416 3

To identify the dynamic transcriptional alterations in CNS during the development of prion disease, brains of scrapie-infected mice and age-matched, mock-inoculated controls were analyzed immediately before inoculation and at different time points post-inoculation using Affymetrix microarray technique. A total of 449 probe sets, representing 430 genes, showed differential expression between scrapie- and mock-inoculated mice over the time course. These genes could be separated into two clusters a ...[more]

PMID: 17437544

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Project description:Background: Prion diseases such as bovine spongiform encephalopathies (BSE) are transmissible neurodegenerative diseases which are presumably caused by an infectious conformational isoform of the cellular prion protein. Previous work has provided evidence that in murine prion disease the endogenous retrovirus (ERV) expression is altered in the brain. To determine if prion-induced changes in ERV expression are a general phenomenon we used a non-human primate model for prion disease. Results: Cynomolgus macaques (Macaca fasicularis) were infected intracerebrally with BSE-positive brain stem material from cattle and allowed to develop prion disease. Brain tissue from the basis pontis and vermis cerebelli of the six animals and the same regions from four healthy controls were subjected to ERV expression profiling using a retrovirus-specific microarray and quantitative real-time PCR. We could show that Class I gammaretroviruses HERV-E4-1, ERV-9, and MacERV-4 increase expression in BSE-infected macaques. In a second approach, we analysed ERV-K-(HML-2) RNA and protein expression in extracts from the same cynomolgus macaques. Here we found a significant downregulation of both, the macaque ERV-K-(HML-2) Gag protein and RNA in the frontal/parietal cortex of BSE-infected macaques. Conclusions: We provide evidence that dysregulation of ERVs in response to BSE-infection can be detected on both, the RNA and the protein level. To our knowledge, this is the first report on the differential expression of ERV-derived structural proteins in prion disorders. Our findings suggest that endogenous retroviruses may induce or exacerbate the pathological consequences of prion-associated neurodegeneration. Cynomolgus macaques (Macaca fasicularis) were infected intracerebrally with BSE-positive brain stem material from cattle and allowed to develop prion disease. Brain tissue from the basis pontis and vermis cerebelli of the six animals and the same regions from four healthy controls were subjected to ERV expression profiling using a retrovirus-specific microarray and quantitative real-time PCR. In a second approach, ERV-K-(HML-2) RNA and protein expression was analysed in extracts from the same cynomolgus macaques.

Project description:Multiple sclerosis (MS) is a chronic, inflammatory, and demyelinating disease of the central nervous system (CNS). Ursolic acid (UA) can be used in the MS treatment with anti-inflammatory and neuroprotective activities. However, UA is insoluble in water, which may affect its medication effectiveness. In this study, we evaluated the pharmacological effects of UAOS-Na, a water-soluble UA derivative, on experimental autoimmune encephalomyelitis (EAE) mouse, explored its underlying mechanism, and verified the mechanism by in vitro and in vivo experiments. As we expected, UAOS-Na (30 mg/kg/d) delayed the onset time of EAE from 11.78 days post immunization (dpi) to 14.33 dpi, reduced the incidence from 90.0% to 42.9%, and was more effective than UA. UAOS-Na (60 mg/kg/d) significantly decreased the serum levels of IFN-γ, IL-17A, TNF-α and IL-6, reduced the mononuclear cell infiltration of spinal cord, and inhibited the overexpression of key transcription factors T-bet and ROR-γt of EAE mouse spinal cord and spleen. In addition, UAOS-Na attenuated demyelination and astrogliosis in the CNS of EAE and Cuprizone-induced mice. Mechanically, proteomics showed that 217 differential expression proteins (DEPs) were enriched and 215 were upregulated in EAE mice. After UAOS-Na treatment, 52 DEPs were enriched and 49 were downregulated, and these DEPs were markedly enriched in inositol phosphate metabolism, calcium, sphingolipid, cAMP, and antigen processing and presentation (APP) signaling pathways. Among them, there were few studies on APP signaling pathway related with MS. Therefore, we further investigated the effect of UAOS-Na on APP signaling pathway and found that UAOS-Na downregulated the protein levels of Tapbp and H2-T23 in MHC-I antigen presentation pathway and decreased the proliferation of splenic CD8 T cells, thereby inhibiting the CNS infiltration of CD8 T cells. Together, our findings demonstrated that UAOS-Na have both direct anti-demyelination and anti-inflammation effects. And it could reduce the inflammation of MS by downregulating the expression of Tapbp and H2-T23 in the MHC-I antigen presentation pathway.

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.

Dataset Information

Transcription profiling of mouse scrapie ME7-infected and mock-infected brains at two important preclinical time points and at terminal stages

Publications

Transcriptome analysis reveals altered cholesterol metabolism during the neurodegeneration in mouse scrapie model.

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