Gene expression analysis in distinct regions of the central nervous system during the development of SSBP/1 sheep...

Rodent scrapie models have been exploited to define the molecular basis for the progression of neuropathological changes in TSE diseases. We aim to assess whether CNS gene expression changes consistently observed in mouse models are of generic relevance, for example to natural TSE diseases, or are TSE strain, host species or brain region specific. Six genes, representing distinct physiological pathways and showing consistent changes in expression levels with disease progression in murine scrapie models were analysed for expression (RT-qPCR) in defined regions of the sheep brain at various times after SSBP/1 scrapie infection. Gene expression was examined in relation to the development of neuropathological changes including PrP(Sc) deposition and vacuolation. Peripheral infection of sheep with SSBP/1 showed consistent progression of neuropathology as assessed by the temporal course of PrP(Sc) deposition and neuropil vacuolation. The first region affected was the medulla (obex), then the thalamus and finally the cerebellum and frontal cortex. In contrast to mouse scrapie, there were few significant changes in transcript expression for any of the six genes and no consistent changes in patterns of expression in relation to brain region, time after infection or neuropathology in sheep SSBP/1. Gene expression changes in mouse TSE models, even changes consistent with the neuropathology, cannot necessarily be extrapolated to species in which disease naturally occurs. This may represent differences in pathological processes of different scrapie strains or across species; and highlights the difficulties in identifying generic molecular pathways associated to the pathogenesis of TSE disease.