Abstract
The pathogenesis of natural scrapie and other prion diseases remains unclear. Examining transcriptome variations in infected versus control animals may highlight new genes potentially involved in some of the molecular mechanisms of prion-induced pathology. The aim of this work was to identify disease-associated alterations in the gene expression profiles of the caudal medulla oblongata (MO) in sheep presenting the symptomatic phase of natural scrapie. The gene expression patterns in the MO from 7 sheep that had been naturally infected with scrapie were compared with 6 controls using a Central Veterinary Institute (CVI) custom designed 4×44K microarray. The microarray consisted of a probe set on the previously sequenced ovine tissue library by CVI and was supplemented with all of the Ovis aries transcripts that are currently publicly available. Over 350 probe sets displayed greater than 2-fold changes in expression. We identified 148 genes from these probes, many of which encode proteins that are involved in the immune response, ion transport, cell adhesion, and transcription. Our results confirm previously published gene expression changes that were observed in murine models with induced scrapie. Moreover, we have identified new genes that exhibit differential expression in scrapie and could be involved in prion neuropathology. Finally, we have investigated the relationship between gene expression profiles and the appearance of the main scrapie-related lesions, including prion protein deposition, gliosis and spongiosis. In this context, the potential impacts of these gene expression changes in the MO on scrapie development are discussed.
Highlights
Scrapie is a transmissible progressive neurodegenerative disease that occurs naturally in sheep and goats and constitutes one of the most widely studied models of transmissible spongiform encephalopathies (TSE) [1], a disease class that includes bovine spongiform encephalopathy (BSE) in cattle and human pathologies such as Creutzfeldt-Jakob disease and Kuru [1,2,3,4]
Spongiosis, PrPSc deposition and glial fibrillary acidic protein (GFAP) immunoreactivity were consistent with the features of classical scrapie [31]
As the reliability of microarray experiments is optimal for fold changes values higher than 1.7, we developed this analysis with genes whose expression was modified at a level equal to or higher than this proportion
Summary
Scrapie is a transmissible progressive neurodegenerative disease that occurs naturally in sheep and goats and constitutes one of the most widely studied models of transmissible spongiform encephalopathies (TSE) [1], a disease class that includes bovine spongiform encephalopathy (BSE) in cattle and human pathologies such as Creutzfeldt-Jakob disease and Kuru [1,2,3,4]. A hallmark of all these diseases is the accumulation of an insoluble and protease-resistant isoform of the host-encoded prion protein (PrP), termed PrPSc. According to the prion hypothesis, PrPSc is the principal component of the infectious particle, which is called a prion [5]. The neuropathology of prion diseases is characterized by the appearance and accumulation of PrPSc in the brain, spongiform degeneration, neuronal loss, and the activation of glial cells [6,7,8,9,10,11,12,13]. Intensive research has aimed to investigate the relationship between the accumulation of prion protein PrPSc, activation of microglia and astrocytes and the pathology of prion disease (e.g., neuronal loss) [12,13,14,15]. Several attempts have been made to understand the molecular events of these diseases [16,17,18], the precise molecular and cellular mechanisms that underlie prion disease pathogenesis, and even the role of PrPC in host species, remain unknown
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