Gene Expression Profiling and Association with Prion-Related Lesions in the Medulla Oblongata of Symptomatic Natural Scrapie Animals

Filali, Hicham; Martín-Burriel, Inmaculada; Harders, Frank; Varona, L.; Lyahyai, Jaber; Zaragoza, Pilar; Pumarola, M.; Badiola, Juan José; Bossers, Alex; Bolea, Rosa

doi:10.1371/journal.pone.0019909

Cited by 20 publications

(46 citation statements)

References 104 publications

(148 reference statements)

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“…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.…”

Section: Discussioncontrasting

confidence: 99%

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

et al. 2014

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BackgroundPrion diseases are characterized by the accumulation of the pathogenic PrPSc protein, mainly in the brain and the lymphoreticular system. Although prions multiply/accumulate in the lymph nodes without any detectable pathology, transcriptional changes in this tissue may reflect biological processes that contribute to the molecular pathogenesis of prion diseases. Little is known about the molecular processes that occur in the lymphoreticular system in early and late stages of prion disease. We performed a microarray-based study to identify genes that are differentially expressed at different disease stages in the mesenteric lymph node of sheep naturally infected with scrapie. Oligo DNA microarrays were used to identify gene-expression profiles in the early/middle (preclinical) and late (clinical) stages of the disease.ResultsIn the clinical stage of the disease, we detected 105 genes that were differentially expressed (≥2-fold change in expression). Of these, 43 were upregulated and 62 downregulated as compared with age-matched negative controls. Fewer genes (50) were differentially expressed in the preclinical stage of the disease. Gene Ontology enrichment analysis revealed that the differentially expressed genes were largely associated with the following terms: glycoprotein, extracellular region, disulfide bond, cell cycle and extracellular matrix. Moreover, some of the annotated genes could be grouped into 3 specific signaling pathways: focal adhesion, PPAR signaling and ECM-receptor interaction. We discuss the relationship between the observed gene expression profiles and PrPSc deposition and the potential involvement in the pathogenesis of scrapie of 7 specific differentially expressed genes whose expression levels were confirmed by real time-PCR.ConclusionsThe present findings identify new genes that may be involved in the pathogenesis of natural scrapie infection in the lymphoreticular system, and confirm previous reports describing scrapie-induced alterations in the expression of genes involved in protein misfolding, angiogenesis and the oxidative stress response. Further studies will be necessary to determine the role of these genes in prion replication, dissemination and in the response of the organism to this disease.

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“…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.…”

Section: Discussioncontrasting

confidence: 99%

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

et al. 2014

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“…In the present study, in the medulla oblongata of a larger set of clinical naturally infected sheep, we confirm the differential expression of the six genes that displayed the largest up- or down-regulation in our previous work [20]: three upregulated (i.e., calpain 6 [ CAPN6 ], galanin 1 [ GALA1 ] and methallothionein 2A [ MT2A ]) and three downregulated genes (i.e., collagen 1 alpha 2 [ COL1A2 ], collagen 3 alpha 1 [ COL3A1 ] and melatonin receptor 1b [ MTNR1B ]). We also extended the analysis to include gene transcription data from three additional CNS regions.…”

Section: Introductionsupporting

confidence: 91%

“…We recently published [20] the gene transcription profiles from the medulla oblongata of sheep, which were naturally infected with clinical scrapie, using a microarray platform. In this study, criteria based on fold-change values, gene ontology and association analyses with PrP Sc deposition, astrocytosis and spongiosis were used to select a set of neuropathology-related genes that had previously been reported to be associated with prion and other neurodegenerative diseases in experimental models [21-26].…”

Section: Introductionmentioning

confidence: 99%

Gene and protein patterns of potential prion-related markers in the central nervous system of clinical and preclinical infected sheep

Filali

Vidal

Bolea

et al. 2013

Vet Res

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The molecular pathogenic mechanisms of prion diseases are far from clear. Genomic analyses have revealed genetic biomarkers potentially involved in prion neuropathology in naturally scrapie-infected sheep, a good animal model of infectious prionopathies. However, these biomarkers must be validated in independent studies at different stages of the disease. The gene and protein expression profiles and protein distribution of six potential genetic biomarkers (i.e., CAPN6, COL1A2, COL3A1, GALA1, MT2A and MTNR1B) are presented here for both the early and terminal stages of scrapie in five different brain regions. Gene transcription changes were confirmed in the medulla oblongata, and the expression profiles were generally similar in other central nervous system regions. The changes were more substantial in clinical animals compared to preclinical animals. The expression of the CAPN6 protein increased in the spinal cord and cerebellum of the clinical and preclinical brains. The distribution of the GALA1 was identified in glial cells from the cerebellum of scrapie-infected animals, GALA1 protein expression was increased in clinical animals in the majority of regions, and the increase of MT2A was in agreement with previous reports. The downregulation of MTNR1B was especially marked in the Purkinje cells. Finally, although collagen genes were downregulated the protein immunostaining did not reveal significant changes between the scrapie-infected and control animals. In conclusion, this study of gene transcription and protein expression and distribution confirm CAPN6, GALA1, MTNR1B and MT2A as potential targets for further prion disease research.

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“…The GO was determined using on-line functional annotation of DAVID Bioinformatics Resources 2008 (NIAID/NIH, USA). Only the genes with a known GO are shown.*Genes chosen for validation by quantitative RT-PCR.**FC values obtained in a previous study developed by our group comparing scrapie-infected animals in a clinical stage and controls [25]. …”

Section: Resultsmentioning

confidence: 99%

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

et al. 2012

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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.

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Gene Expression Profiling and Association with Prion-Related Lesions in the Medulla Oblongata of Symptomatic Natural Scrapie Animals

Cited by 20 publications

References 104 publications

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

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

Gene and protein patterns of potential prion-related markers in the central nervous system of clinical and preclinical infected sheep

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

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