Dataset Information

Genes contributing to prion pathogenesis.

ABSTRACT: Prion diseases are caused by conversion of a normally folded, non-pathogenic isoform of the prion protein (PrP(C)) to a misfolded, pathogenic isoform (PrP(Sc)). Prion inoculation experiments in mice expressing homologous PrP(C) molecules on different genetic backgrounds displayed different incubation times, indicating that the conversion reaction may be influenced by other gene products. To identify genes that contribute to prion pathogenesis, we analysed incubation times of prions in mice in which the gene product was inactivated, knocked out or overexpressed. We tested 20 candidate genes, because their products either colocalize with PrP, are associated with Alzheimer's disease, are elevated during prion disease, or function in PrP-mediated signalling, PrP glycosylation, or protein maintenance. Whereas some of the candidates tested may have a role in the normal function of PrP(C), our data show that many genes previously implicated in prion replication have no discernible effect on the pathogenesis of prion disease. While most genes tested did not significantly affect survival times, ablation of the amyloid beta (A4) precursor protein (App) or interleukin-1 receptor, type I (Il1r1), and transgenic overexpression of human superoxide dismutase 1 (SOD1) prolonged incubation times by 13, 16 and 19 %, respectively.

SUBMITTER: Tamguney G

PROVIDER: S-EPMC2828448 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genes contributing to prion pathogenesis.

Tamgüney Gültekin G Giles Kurt K Glidden David V DV Lessard Pierre P Wille Holger H Tremblay Patrick P Groth Darlene F DF Yehiely Fruma F Korth Carsten C Moore Richard C RC Tatzelt Jörg J Rubinstein Eric E Boucheix Claude C Yang Xiaoping X Stanley Pamela P Lisanti Michael P MP Dwek Raymond A RA Rudd Pauline M PM Moskovitz Jackob J Epstein Charles J CJ Cruz Tracey Dawson TD Kuziel William A WA Maeda Nobuyo N Sap Jan J Ashe Karen Hsiao KH Carlson George A GA Tesseur Ina I Wyss-Coray Tony T Mucke Lennart L Weisgraber Karl H KH Mahley Robert W RW Cohen Fred E FE Prusiner Stanley B SB

The Journal of general virology 20080701 Pt 7

Prion diseases are caused by conversion of a normally folded, non-pathogenic isoform of the prion protein (PrP(C)) to a misfolded, pathogenic isoform (PrP(Sc)). Prion inoculation experiments in mice expressing homologous PrP(C) molecules on different genetic backgrounds displayed different incubation times, indicating that the conversion reaction may be influenced by other gene products. To identify genes that contribute to prion pathogenesis, we analysed incubation times of prions in mice in wh ...[more]

PMID: 18559949

Similar Datasets

Project description:Background: Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disease. Owing to its high fatality rate and narrow therapeutic options, identification of the pathogenic mechanisms of IPAH is becoming increasingly important. Methods: In our research, we utilized the robust rank aggregation (RRA) method to integrate four eligible pulmonary arterial hypertension (PAH) microarray datasets and identified the significant differentially expressed genes (DEGs) between IPAH and normal samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed to analyze their functions. The interaction network of protein-protein interaction (PPI) was constructed to explore the correlation between these DEGs. The functional modules and hub genes were further identified by the weighted gene coexpression network analysis (WGCNA). Moreover, a miRNA microarray dataset was involved and analyzed to filter differentially expressed miRNAs (DE-miRNAs). Potential target genes of screened DE-miRNAs were predicted and merged with DEGs to explore a miRNA-mRNA network in IPAH. Some hub genes were selected and validated by RT-PCR in lung tissues from the PAH animal model. Results: A total of 260 DEGs, consisting of 183 upregulated and 77 downregulated significant DEGs, were identified, and some of those genes were novel. Their molecular roles in the etiology of IPAH remained vague. The most crucial functional module involved in IPAH is mainly enriched in biological processes, including leukocyte migration, cell chemotaxis, and myeloid leukocyte migration. Construction and analysis of the PPI network showed that CXCL10, CXCL9, CCR1, CX3CR1, CX3CL1, CXCR2, CXCR1, PF4, CCL4L1, and ADORA3 were recognized as top 10 hub genes with high connectivity degrees. WGCNA further identified five main functional modules involved in the pathogenesis of IPAH. Twelve upregulated DE-miRNAs and nine downregulated DE-miRNAs were identified. Among them, four downregulated DEGs and eight upregulated DEGs were supposed to be negatively regulated by three upregulated DE-miRNAs and three downregulated DE-miRNAs, respectively. Conclusions: This study identifies some key and functional coexpression modules involved in IPAH, as well as a potential IPAH-related miRNA-mRNA regulated network. It provides deepening insights into the molecular mechanisms and provides vital clues in seeking novel therapeutic targets for IPAH.

Dataset Information

Genes contributing to prion pathogenesis.

Publications

Genes contributing to prion pathogenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets