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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

Identification of biologically relevant networks. (a) Top ranking network generated by mapping the focus genes that were differentially expressed in infected animals. Pathway analysis based on the Ingenuity Pathway Knowledge Base (IPKB) is shown. Color shading corresponds to the type of dysregulation: red for up-regulated and green for down-regulated genes according to the microarray fold change calculation method. White open nodes are not from the list of 300 DEGs, but are transcription factors that are associated with the regulation of some of these genes identified by IPKB. The shape of the node indicates the major function of the protein. A line denotes binding of the products of the two genes, while a line with an arrow denotes 'acts on'. A dotted line denotes an indirect interaction. (b) Schematic representation of nervous system-related functions for selected DEGs. The most regulated/interesting DEGs were selected and associated to known nervous system-related functions according to the Ingenuity Pathway Knowledge Base (IPKB) software.
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Fig3: Identification of biologically relevant networks. (a) Top ranking network generated by mapping the focus genes that were differentially expressed in infected animals. Pathway analysis based on the Ingenuity Pathway Knowledge Base (IPKB) is shown. Color shading corresponds to the type of dysregulation: red for up-regulated and green for down-regulated genes according to the microarray fold change calculation method. White open nodes are not from the list of 300 DEGs, but are transcription factors that are associated with the regulation of some of these genes identified by IPKB. The shape of the node indicates the major function of the protein. A line denotes binding of the products of the two genes, while a line with an arrow denotes 'acts on'. A dotted line denotes an indirect interaction. (b) Schematic representation of nervous system-related functions for selected DEGs. The most regulated/interesting DEGs were selected and associated to known nervous system-related functions according to the Ingenuity Pathway Knowledge Base (IPKB) software.

Mentions: To further investigate the global expression response to BSE infection and to define interactions among the identified specific pathways containing the regulated genes, potential networks of interacting DEGs were identified using IPA®. All potential networks with score > 9 (a score ≥ 3 was considered significant, p < 0.001) are listed in Table 1 with information on network genes, score, focus molecules and top functions associated with the focus genes in each network. The highest ranked network identified by IPA® was associated with tissue morphology (specifically the determination of cell quantity), developmental disorder and biological processes controlling cell death and survival (Figure 3a). This network contained genes that are known to be involved in several neurological diseases and nervous system functions, as shown in Figure 3b.Table 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)

Identification of biologically relevant networks. (a) Top ranking network generated by mapping the focus genes that were differentially expressed in infected animals. Pathway analysis based on the Ingenuity Pathway Knowledge Base (IPKB) is shown. Color shading corresponds to the type of dysregulation: red for up-regulated and green for down-regulated genes according to the microarray fold change calculation method. White open nodes are not from the list of 300 DEGs, but are transcription factors that are associated with the regulation of some of these genes identified by IPKB. The shape of the node indicates the major function of the protein. A line denotes binding of the products of the two genes, while a line with an arrow denotes 'acts on'. A dotted line denotes an indirect interaction. (b) Schematic representation of nervous system-related functions for selected DEGs. The most regulated/interesting DEGs were selected and associated to known nervous system-related functions according to the Ingenuity Pathway Knowledge Base (IPKB) software.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: Identification of biologically relevant networks. (a) Top ranking network generated by mapping the focus genes that were differentially expressed in infected animals. Pathway analysis based on the Ingenuity Pathway Knowledge Base (IPKB) is shown. Color shading corresponds to the type of dysregulation: red for up-regulated and green for down-regulated genes according to the microarray fold change calculation method. White open nodes are not from the list of 300 DEGs, but are transcription factors that are associated with the regulation of some of these genes identified by IPKB. The shape of the node indicates the major function of the protein. A line denotes binding of the products of the two genes, while a line with an arrow denotes 'acts on'. A dotted line denotes an indirect interaction. (b) Schematic representation of nervous system-related functions for selected DEGs. The most regulated/interesting DEGs were selected and associated to known nervous system-related functions according to the Ingenuity Pathway Knowledge Base (IPKB) software.
Mentions: To further investigate the global expression response to BSE infection and to define interactions among the identified specific pathways containing the regulated genes, potential networks of interacting DEGs were identified using IPA®. All potential networks with score > 9 (a score ≥ 3 was considered significant, p < 0.001) are listed in Table 1 with information on network genes, score, focus molecules and top functions associated with the focus genes in each network. The highest ranked network identified by IPA® was associated with tissue morphology (specifically the determination of cell quantity), developmental disorder and biological processes controlling cell death and survival (Figure 3a). This network contained genes that are known to be involved in several neurological diseases and nervous system functions, as shown in Figure 3b.Table 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