Illumina Solexa digital gene expression and Affymetrix Ovine Gene 1.1 ST Array data of New Zealand Cheviot sheep, homozygous at V(136), R (154) and Q (171) of the PRNP (prion) gene.
Sheep scrapie is a transmissible spongiform encephalopathy (TSE), progressive and fatal neurodegenerative diseases of the central nervous system (CNS) linked to the accumulation of misfolded prion protein, PrPSc. New Zealand Cheviot sheep, homozygous for the VRQ genotype of the PRNP gene are most susceptible with an incubation period of 193 days with SSBP/1 scrapie. However, the earliest time point that PrPSc can be detected in the CNS is 125 days (D125). The aim of this study was to quantify changes to the transcriptome of the thalamus and obex (medulla) at times immediately before (D75) and after (D125) PrPSc was detected. Affymetrix gene arrays were used to quantify gene expression in the thalamus and Illumina DGE-tag profiling for obex. Ingenuity Pathway Analysis was used to help describe the biological processes of scrapie pathology.
Neurological disease and Cancer were common Bio Functions in each tissue at D75; inflammation and cell death were major processes at D125. Several neurological receptors were significantly increased at D75 (e.g. CHRNA6, GRM1, HCN2), which might be clues to the molecular basis of psychiatric changes associated with TSEs. No genes were significantly differentially expressed at both D75 and D125 and there was no progression of events from earlier to later time points. This implies that there is no simple linear progression of pathological or molecular events. There seems to be a step-change between D75 and D125, correlating with the detection of PrPSc, resulting in the involvement of
different pathological processes in later TSE disease.
For many transmissible spongiform encephalopathies (TSEs),
peripheral lymphoid tissue is an important site of PrPSc amplification but without gross immunological consequence. Susceptible VRQ homozygous New Zealand Cheviot sheep were infected with SSBP/1 scrapie by inoculation in the drainage area of the prescapular lymph nodes. The earliest time that PrPSc was consistently detected by immunohistology in these nodes was D50 post infection. This transcriptomic study of lymph node taken before (D10) and after (D50) the detection of PrPSc, aimed to identify the genes and physiological pathways affected by disease progression within the nodes as assessed by PrPSc detection. Affymetrix Ovine Gene arrays identified 75 and 80 genes as differentially-expressed at D10 and D50, respectively, in comparison with control sheep inoculated with uninfected brain homogenate. Approximately 70% of these were repressed at each time point. RT-qPCR analysis of seven genes showed statistically significant correlation with the array data, although the results for IL1RN and TGIF were different between the two technologies. The ingenuity pathway analysis (IPA) and general low level of repression of gene expression in lymphoid tissue, including many inflammatory genes, contrasts with the pro-inflammatory and pro-apoptotic events that occur within the CNS at equivalent
stages of disease progression as assessed by PrPSc accumulation.
1. Gossner, A. G. and J. Hopkins. (2014). Transcriptome analysis of CNS immediately before and after the detection of PrPSc in sheep scrapie. Vet Microbiol 173, 201-207. PMID: 25183238, doi:10.1016/j.vetmic.2014.07.026.
2. Gossner, A. G. and J. Hopkins. (2015). The effect of PrPSc accumulation on inflammatory gene expression within sheep peripheral lymphoid tissue. Vet Microbiol 181, 204–211. PMID: 26507419, doi:10.1016/j.vetmic.2015.10.013.
|Date made available||2017|
|Temporal coverage||1 Oct 2005 - 13 Oct 2015|
|Date of data production||2011 - 2013|