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Gene expression profiling of brains from bovine spongiform encephalopathy (BSE)-infected cynomolgus macaques.

Barbisin M, Vanni S, Schmädicke AC, Montag J, Motzkus D, Opitz L, Salinas-Riester G, Legname G - BMC Genomics (2014)

Bottom Line: The results obtained with the microarray technology were confirmed and a gene signature was identified.Some genes involved in oxygen or lipid transport and in innate immunity were found to be dysregulated in prion infected macaques.Our results may facilitate the identification of potential disease biomarkers for many neurodegenerative diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Via Bonomea 265, 34136 Trieste, Italy. legname@sissa.it.

ABSTRACT

Background: Prion diseases are fatal neurodegenerative disorders whose pathogenesis mechanisms are not fully understood. In this context, the analysis of gene expression alterations occurring in prion-infected animals represents a powerful tool that may contribute to unravel the molecular basis of prion diseases and therefore discover novel potential targets for diagnosis and therapeutics. Here we present the first large-scale transcriptional profiling of brains from BSE-infected cynomolgus macaques, which are an excellent model for human prion disorders.

Results: The study was conducted using the GeneChip® Rhesus Macaque Genome Array and revealed 300 transcripts with expression changes greater than twofold. Among these, the bioinformatics analysis identified 86 genes with known functions, most of which are involved in cellular development, cell death and survival, lipid homeostasis, and acute phase response signaling. RT-qPCR was performed on selected gene transcripts in order to validate the differential expression in infected animals versus controls. The results obtained with the microarray technology were confirmed and a gene signature was identified. In brief, HBB and HBA2 were down-regulated in infected macaques, whereas TTR, APOC1 and SERPINA3 were up-regulated.

Conclusions: Some genes involved in oxygen or lipid transport and in innate immunity were found to be dysregulated in prion infected macaques. These genes are known to be involved in other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Our results may facilitate the identification of potential disease biomarkers for many neurodegenerative diseases.

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Related in: MedlinePlus

Correlation between PrPSccontent and duration of clinical phase. Western Blot analysis from PK-treated homogenates of brain samples derived from BSE-infected macaques was performed. The monoglycosylated bands of PrPSc were analyzed densitometrically. Relative amounts of PrPSc from brain homogenates were averaged and correlated to the disease duration.
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Fig1: Correlation between PrPSccontent and duration of clinical phase. Western Blot analysis from PK-treated homogenates of brain samples derived from BSE-infected macaques was performed. The monoglycosylated bands of PrPSc were analyzed densitometrically. Relative amounts of PrPSc from brain homogenates were averaged and correlated to the disease duration.

Mentions: The relative amount of PrPSc in brain homogenate of 6 BSE-infected macaques was examined by Western Blot. Densitometric analysis of the monoglycosylated band revealed that the relative amount of PrPSc strongly differed between the individual macaques. We wondered whether this discrepancy might be due to the preclinical incubation time or rather correspond to the gradual accumulation of PrPSc during the clinical phase of disease as reported for sCJD [38, 39]. As anticipated, we found a significant correlation between PrPSc content and the duration of the symptomatic phase (Figure 1). The correlation analysis includes only the 6 intracranially inoculated macaques. Since these animals were housed in one social group, environmental factors, which may influence the disease course and duration, are identical. Such factors can be different for the orally inoculated animal, which was therefore omitted from the analysis. The infected animals were at an advanced stage of prion disease and the details of their clinical course have been previously described [33]. Briefly, animal A1 showed the shortest duration of disease (17 days) and a short pre-clinical incubation time (931 days) together with the lowest PrPSc content, while animal A5 showed the longest survival period (143 days), compared to an average clinical phase of about 90 days, together with the highest PrPSc content and the second longest pre-clinical phase (1340 days).Figure 1


Gene expression profiling of brains from bovine spongiform encephalopathy (BSE)-infected cynomolgus macaques.

Barbisin M, Vanni S, Schmädicke AC, Montag J, Motzkus D, Opitz L, Salinas-Riester G, Legname G - BMC Genomics (2014)

Correlation between PrPSccontent and duration of clinical phase. Western Blot analysis from PK-treated homogenates of brain samples derived from BSE-infected macaques was performed. The monoglycosylated bands of PrPSc were analyzed densitometrically. Relative amounts of PrPSc from brain homogenates were averaged and correlated to the disease duration.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4061447&req=5

Fig1: Correlation between PrPSccontent and duration of clinical phase. Western Blot analysis from PK-treated homogenates of brain samples derived from BSE-infected macaques was performed. The monoglycosylated bands of PrPSc were analyzed densitometrically. Relative amounts of PrPSc from brain homogenates were averaged and correlated to the disease duration.
Mentions: The relative amount of PrPSc in brain homogenate of 6 BSE-infected macaques was examined by Western Blot. Densitometric analysis of the monoglycosylated band revealed that the relative amount of PrPSc strongly differed between the individual macaques. We wondered whether this discrepancy might be due to the preclinical incubation time or rather correspond to the gradual accumulation of PrPSc during the clinical phase of disease as reported for sCJD [38, 39]. As anticipated, we found a significant correlation between PrPSc content and the duration of the symptomatic phase (Figure 1). The correlation analysis includes only the 6 intracranially inoculated macaques. Since these animals were housed in one social group, environmental factors, which may influence the disease course and duration, are identical. Such factors can be different for the orally inoculated animal, which was therefore omitted from the analysis. The infected animals were at an advanced stage of prion disease and the details of their clinical course have been previously described [33]. Briefly, animal A1 showed the shortest duration of disease (17 days) and a short pre-clinical incubation time (931 days) together with the lowest PrPSc content, while animal A5 showed the longest survival period (143 days), compared to an average clinical phase of about 90 days, together with the highest PrPSc content and the second longest pre-clinical phase (1340 days).Figure 1

Bottom Line: The results obtained with the microarray technology were confirmed and a gene signature was identified.Some genes involved in oxygen or lipid transport and in innate immunity were found to be dysregulated in prion infected macaques.Our results may facilitate the identification of potential disease biomarkers for many neurodegenerative diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Via Bonomea 265, 34136 Trieste, Italy. legname@sissa.it.

ABSTRACT

Background: Prion diseases are fatal neurodegenerative disorders whose pathogenesis mechanisms are not fully understood. In this context, the analysis of gene expression alterations occurring in prion-infected animals represents a powerful tool that may contribute to unravel the molecular basis of prion diseases and therefore discover novel potential targets for diagnosis and therapeutics. Here we present the first large-scale transcriptional profiling of brains from BSE-infected cynomolgus macaques, which are an excellent model for human prion disorders.

Results: The study was conducted using the GeneChip® Rhesus Macaque Genome Array and revealed 300 transcripts with expression changes greater than twofold. Among these, the bioinformatics analysis identified 86 genes with known functions, most of which are involved in cellular development, cell death and survival, lipid homeostasis, and acute phase response signaling. RT-qPCR was performed on selected gene transcripts in order to validate the differential expression in infected animals versus controls. The results obtained with the microarray technology were confirmed and a gene signature was identified. In brief, HBB and HBA2 were down-regulated in infected macaques, whereas TTR, APOC1 and SERPINA3 were up-regulated.

Conclusions: Some genes involved in oxygen or lipid transport and in innate immunity were found to be dysregulated in prion infected macaques. These genes are known to be involved in other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Our results may facilitate the identification of potential disease biomarkers for many neurodegenerative diseases.

Show MeSH
Related in: MedlinePlus