PrP gene and its association with spongiform encephalopathies.

The PrP or prion protein plays a key role in the pathogenesis of the transmissible spongiform encephalopathies. This 33-35 kD sialoglycoprotein is the product of a single host gene which is composed of 2 or 3 exons, a single open reading frame and a cytidine/guanidine rich promoter. The structure of the gene and the sequence of the protein are highly conserved in various mammals. Primarily, transcription of the PrP gene is found in neurons of the central and peripheral nervous system but other tissues do express PrP at least at some stages of development. Translation of the PrP mRNA and processing of the initial gene product result in a 210 amino acid protein with asparagine-linked glycosylation of the complex type which attaches itself to the outer leaflet of the plasma membrane lipid bilayer by a C-terminal glycosylinositol phospholipid. The function of this protein is unknown. Development of the transmissible spongiform encephalopathies, and increasing titre of the causative pathogen, are associated with the accumulation in and around cells of pleiomorphic aggregates of PrP which are partially resistant to proteolytic hydrolysis. These abnormal deposits of PrP, and the normal isoform, are transcribed from the same gene and so any disease-linked modification of the protein must be post-transcriptional. No disease-specific, covalent modifications of PrP have yet been found and some simple, conformational change in its secondary, tertiary (or quaternary) structure may underlie its role in these diseases. Polymorphisms in the PrP gene of different species have been associated with disease but none of these changes in primary structure appear to cause protease resistance per se. Preclinical inference of disease susceptibility can already be made using PrP genotype analysis in man and some animals but developing a cure for these diseases, whether by drug or gene therapy, will require a much greater understanding of the molecular and cell biology of this gene and its products. This article presents current views and understanding of the PrP gene.