Abstract
BackgroundThe pathogenesis of natural scrapie and other prion diseases is still poorly understood. Determining the variations in the transcriptome in the early phases of the disease might clarify some of the molecular mechanisms of the prion-induced pathology and allow for the development of new biomarkers for diagnosis and therapy. This study is the first to focus on the identification of genes regulated during the preclinical phases of natural scrapie in the ovine medulla oblongata (MO) and the association of these genes with prion deposition, astrocytosis and spongiosis.ResultsA custom microarray platform revealed that 86 significant probes had expression changes greater than 2-fold. From these probes, we identified 32 genes with known function; the highest number of regulated genes was included in the phosphoprotein-encoding group. Genes encoding extracellular marker proteins and those involved in the immune response and apoptosis were also differentially expressed. In addition, we investigated the relationship between the gene expression profiles and the appearance of the main scrapie-associated brain lesions. Quantitative Real-time PCR was used to validate the expression of some of the regulated genes, thus showing the reliability of the microarray hybridization technology.ConclusionsGenes involved in protein and metal binding and oxidoreductase activity were associated with prion deposition. The expression of glial fibrillary acidic protein (GFAP) was associated with changes in the expression of genes encoding proteins with oxidoreductase and phosphatase activity, and the expression of spongiosis was related to genes encoding extracellular matrix components or transmembrane transporters. This is the first genome-wide expression study performed in naturally infected sheep with preclinical scrapie. As in previous studies, our findings confirm the close relationship between scrapie and other neurodegenerative diseases.
Highlights
The pathogenesis of natural scrapie and other prion diseases is still poorly understood
We report here the first transcriptome study of the central nervous system (CNS) in sheep naturally infected with scrapie in preclinal stages that associated the variations in the expression profile with the features of scrapie neuropathology
Further analyses are necessary to confirm their differential regulation in a wider number of animals or in different prion animal models, these custom sequences can represent potential unknown biomarkers useful for the diagnosis of presymptomatic prion disease. In summary, this is the first genome-wide expression study performed in naturally infected sheep with preclinical scrapie and shows the induction of a reduced number of genes compared with the changes shown in clinical scrapie sheep
Summary
The pathogenesis of natural scrapie and other prion diseases is still poorly understood. Determining the variations in the transcriptome in the early phases of the disease might clarify some of the molecular mechanisms of the prion-induced pathology and allow for the development of new biomarkers for diagnosis and therapy. Scrapie is a prion-associated encephalopathy that occurs naturally in sheep and goats. It is characterized by the accumulation of a pathological agent, the prion protein (PrPSc), mainly in the central nervous system [1]. PrPSc can be detected in VRQ/VRQ sheep, genotype for the PRNP gene, two months after infection [7]. Three to six months after infection, the pathological agent is detected in the lymphoid formations associated with the gastrointestinal tract [8,9]. From six to nine months, the secondary lymphoid organs are infected, and at the tenth month after infection, the central nervous system is affected [10,11,12]
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