Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Expression data for inbred mouse brains

ABSTRACT: Prion diseases are fatal neurodegenerative disorders that include bovine spongiform encephalopathy (BSE) and scrapie in animals and Creutzfeldt-Jakob disease (CJD) in humans. They are characterized by long incubation periods, variation in which is determined by many factors including genetic background. In some cases it is possible that incubation time may be directly correlated to the level of gene expression. In order to test this hypothesis we combined incubation time data from five different inbred lines of mice with quantitative gene expression profiling in normal brains and identified five genes with expression levels that correlate with incubation time. One of these genes, Hspa13 (Stch), is a member of the Hsp70 family of ATPase heat shock proteins which have been previously implicated in prion propagation. To test whether Hspa13 plays a causal role in determining the incubation period we tested two over-expressing mouse models. The Tc1 human chromosome 21 (Hsa21) transchromosomic mouse model of Down syndrome is trisomic for many Hsa21 genes including Hspa13 and following Chandler/RML prion inoculation shows a 4% reduction in incubation time. Furthermore, a transgenic model with eight fold over-expression of mouse Hspa13 exhibited highly significant reductions in incubation time of 16%, 15% and 7% following infection with Chandler/RML, ME7 and MRC2 prion strains respectively. These data further implicate Hsp70-like molecular chaperones in protein misfolding disorders such as prion disease. 5 inbred lines of mice, 5 samples for each line

ORGANISM(S): Mus musculus

SUBMITTER: Sarah Lloyd

PROVIDER: E-GEOD-38205 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Overexpression of the Hspa13 (Stch) gene reduces prion disease incubation time in mice.

Grizenkova Julia J Akhtar Shaheen S Hummerich Holger H Tomlinson Andrew A Asante Emmanuel A EA Wenborn Adam A Fizet Jérémie J Poulter Mark M Wiseman Frances K FK Fisher Elizabeth M C EM Tybulewicz Victor L J VL Brandner Sebastian S Collinge John J Lloyd Sarah E SE

Proceedings of the National Academy of Sciences of the United States of America 20120806 34

Prion diseases are fatal neurodegenerative disorders that include bovine spongiform encephalopathy (BSE) and scrapie in animals and Creutzfeldt-Jakob disease (CJD) in humans. They are characterized by long incubation periods, variation in which is determined by many factors including genetic background. In some cases it is possible that incubation time may be directly correlated to the level of gene expression. To test this hypothesis, we combined incubation time data from five different inbred ...[more]

PMID: 22869728

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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 cell types and complex connection networks are an intrinsic feature of brain tissue. In this study we used expression profiling of homogeneous cell populations from specific microscopic regions of heterogeneous tissue sections isolated by laser capture microdissection (LCM) to determine insights into the molecular basis of brain pathology in prion disease. Temporal profiles in two mouse models of prion disease, bovine spongiform encephalopathy (BSE) and a mouse-adapted strain of scrapie (RML) were performed in microdissected regions of the CA1 and cerebellar granular that are enriched in neuronal cell bodies. We noted that during clinical disease the number of activated microglia and astrocytes that occur in these areas are increased, thereby likely diluting the neuronal gene expression signature. We performed a comparative analysis with gene expression profiles determined from isolated populations of neurons, microglia and astrocytes to identify transcripts that are enriched in each of these cell types. Although the incubation periods of these two models are quite different, over 300 days for BSE and ~160 days for RML scrapie, these regional microdissections revealed broadly similar profiles. Microglial and astrocyte-enriched genes contributed a profound inflammatory profile consisting of inflammatory cytokines, genes related to phagocytosis, proteolysis and genes coding for extracellular matrix proteins. CA1 pyramidal neurons displayed a net upregulation of transcription factors and stress induced genes at pre-clinical stages of disease while all tissues showed profound downregulation of overlapping genes related to neuronal function, in particular transcripts related to neuronal communication including glutamate receptors, phosphatase subunits and numerous synaptic-related markers. Of note we found a small number of genes expressed in neurons that were upregulated during clinical disease including, COX6A, FZD9, RXRG and SOX11, that may be useful biomarkers of neurodegeneration.

Dataset Information

Expression data for inbred mouse brains

Publications

Overexpression of the Hspa13 (Stch) gene reduces prion disease incubation time in mice.

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