Medulla oblongata transcriptome changes during presymptomatic natural scrapie and their association with prion-related lesions

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.

Gene expression profiling of mesenteric lymph nodes from sheep with natural scrapie

“…Similarly, our results differ from the profiles described in the brains of sheep with natural scrapie [10,11], indicating the absence of universal changes associated with prion infection.…”

The effect of PrP Sc accumulation on inflammatory gene expression within sheep peripheral lymphoid tissue

“…Firstly, scrapie infection of the lymph node leads to the general down-regulation of genes and in particular is associated with the repression of inflammation at both D10 and D50. This contrasts with the effects of sheep scrapie-infection in the CNS, where studies ( Filali et al, 2012 , Gossner and Hopkins, 2014 , Xiang et al, 2004 ) showed consistent increases in genes promoting complement fixation, inflammation and cell death/apoptosis as well as regulation of cell growth/cancer. Secondly, lymph nodes react to scrapie agent as early as 10 days after infection and this reaction is not related to the detectable accumulation of PrP Sc .…”

“…The effects of PrP Sc accumulation on the CNS transcriptome has been investigated in several different species, including mice ( Xiang et al, 2004 ), cattle ( Almeida et al, 2011 ), sheep ( Filali et al, 2012 , Gossner and Hopkins, 2014 ) and humans ( Tian et al, 2013 ) with the aim of identifying genes associated with TSE disease progression. Similar analysis of secondary lymphoid tissues is so far limited to two sheep studies; an investigation on mesenteric lymph node in natural scrapie ( Filali et al, 2014 ) and our preliminary study ( Gossner et al, 2011b ) on SSBP/1 scrapie.…”

Biomarcadores asociados con scrapie y otras encefalopatías espongiformes transmisibles

“…Se han realizado pocos estudios sobre los cambios de los perfiles de expresión génica en tejidos procedentes de individuos afectados de forma natural por EETs, como el scrapie ovino (Cosseddu et al, 2007;Filali et al, 2011;Filali et al, 2012), la EEB (Khaniya et al, 2009), la EDC (Basu et al, 2012) o la ECJ humana (Xiang et al, 2005). Las prionopatías naturales han sido poco estudiadas debido a la rareza de los casos humanos, los problemas de heterogeneidad de muestras generadas en ámbitos naturales de las distintas enfermedades y la facilidad que supone el trabajo en roedores en comparación con los grandes animales.…”