Transcriptome analysis of CNS immediately before and after the detection of PrPSc in SSBP/1 sheep scrapie

Anton G Gossner,John Hopkins

doi:10.1016/j.vetmic.2014.07.026

Abstract

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.

Highlights

Sheep scrapie is a transmissible spongiform encephalopathy (TSEs); fatal diseases of the central nervous system (CNS) that includes Creutzfeldt Jakob Disease (CJD) in humans, chronic wasting disease in deer and bovine spongiform encephalopathy (BSE)
The thalamus and obex are both sites of scrapie pathology (Gonzalez et al, 2003) and PrPSc aggregation can be detected for the first time in both tissues at D125 (Gossner et al, 2011a)
Transcriptome analysis of the thalamus was by the Affymetrix Ovine gene 1.1 ST Array, which consists of probes for all exons in each annotated transcript of the OARv2 sheep genome assembly

Summary

Introduction

Sheep scrapie is a transmissible spongiform encephalopathy (TSEs); fatal diseases of the central nervous system (CNS) that includes Creutzfeldt Jakob Disease (CJD) in humans, chronic wasting disease in deer and bovine spongiform encephalopathy (BSE). The principal pathological features of these diseases are neural cell degeneration, spongiform change and glial cell hypertrophy (Prusiner et al, 1998) that are linked to the conversion of the normal cellular prion protein (PrPC, encoded by the PRNP gene) to the disease-associated conformer PrPSc (Prusiner, 1982). The central role of PrPC in scrapie is illustrated by the fact that PRNP knockout mice are resistant to disease (Bueler et al, 1993) and by the reciprocal relationship between PRNP copy number and incubation period (Bueler et al, 1993). Susceptibility to scrapie in sheep is controlled by PRNP genotype (Goldmann et al, 1994) at codons 136, 154 and 171; in Cheviot sheep ARR/ARR animals are resistant, VRQ homozygotes have the shortest incubation period and heterozygotes are intermediate.

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