Genetics of transmissible spongiform encephalopathy susceptibility and the search for surrogate markers for infection
Authors: Williams J. L. 
Published: December 2004

The transmissible spongiform encephalopathy diseases are unusual in that they can be sporadic or infectious, and that the infectious agent does not contain nucleic acids. Instead, infectivity is associated with a modified host-encoded protein referred to as a prion. During the course of disease, host encoded prion protein (PrP) is converted from the normal cellular form, PrPC, to a disease form, PrPSC/BSE, which is highly resistant to degradation by heat or proteinases. The occurrence of the sporadic form of transmissible spongiform encephalopathy disease in humans, as well as susceptibility to infection in humans and some animal species has been correlated with particular alleles of the host PrP gene. Scrapie has been endemic in sheep populations in many countries for over 100 years, with no apparent adverse effects on human health, however the occurrence of bovine spongiform encephalopathy in the mid 1980s in the United Kingdom and subsequently other countries has stimulated interest in the transmissible spongiform encephalopathy diseases. Bovine spongiform encephalopathy seems to have arisen from the recycling of ruminant offals, although it is not clear whether bovine spongiform encephalopathy was already endemic in the cattle population and this practice simply increased the incidence, or if the disease was newly introduced to cattle by transmission of scrapie from sheep. A new form of Creutzfeldt-Jacob disease that bares all the hallmarks of bovine spongiform encephalopathy was recently described in humans, suggesting that it arose from consumption of bovine spongiform encephalopathy-infected beef. Subsequent studies have demonstrated that transmissible spongiform encephalopathy disease can be experimentally transmitted between species and has alerted us to the potential risk of allowing scrapie to remain in the sheep population. In the United Kingdom, the sheep population is being PrP-genotyped and breeding stock selected from animals with genotypes that have been shown to be more resistant to scrapie. However, the resistant sheep genotypes may still harbour disease. There is no convincing evidence for PrP genotypes in cattle that are resistant to bovine spongiform encephalopathy. Work in cattle and mice has shown that there are loci other than PrP that influence the host response to a transmissible spongiform encephalopathy challenge. In order to monitor, and ultimately control, transmissible spongiform encephalopathy diseases in livestock it is important to identify markers for infection that are robust, appear early in infection and can be measured in an easily obtained sample, such as blood. We have developed a bovine ‘non-redundant’ cDNA set from brain to allow expression profiling using macro- and micro array technology. The identities of genes represented the in the non-redundant cDNAs set were assigned by oligo-nucleotide fingerprinting and have been confirmed by sequencing. This non-redundant cDNA set has been used to create a bovine array that is being used to examine expression in tissues from cattle during a time course of experimental bovine spongiform encephalopathy infection in order to identify genes with expression profiles that are altered following infection. Such genes may provide surrogate markers to detect transmissible spongiform encephalopathy infection during the early stages of disease. Ultimately knowledge of such genes may suggest targets for pharmacological intervention to arrest the disease process before the onset of the major neurological damage associated with the terminal stage of the disease.