Biochemical analysis of peripheral tissue involvement in transmissible spongiform encephalopathies
V. A. Lawson^', A. F. Hill''^'\ V. Lewis''^^ R. Sharpies''^', S. Collins'''^
and C. L. Masters^'^'"^
^Department of Pathology, ^School of Biochemistry and Molecular Biol- ogy, ^Australian National Creutzfeldt-Jakob Disease Registry, "^Mental Health Research Institute, The University of Melbourne, Parkville, Austra- lia 3010 <e-mail> [email protected]
Abstract
Transmissible spongiform encephalopathies (TSE) are transmissible, neu- rodegenerative disorders affecting humans and animals. Although the etiological agent of TSE has yet to be conclusively identified, a unifying feature is the accumulation of an abnormal protease-resistant isomer (PrP^'') of the host encoded prion protein (PrP^). PrP^ expression is re- quired for the transmission and pathogenesis of TSE disease. Despite the ubiquitous organ distribution of PrP^, TSE pathogenesis and infectivity is principally restricted to the central nervous and lymphoreticular systems.
However, recent studies have highlighted the presence of low levels of PrP^^ and TSE infectivity in some peripheral tissues including muscle and the possible transmission of variant Creutzfeldt Jakob disease through blood transfusion. This has raised concerns regarding the risk of iatro- genic transmission of TSE disease through surgical procedures and organ or blood donation.
Several assays have been developed to study the conformational change that accompanies the conversion of PrP^ to PrP^^. These include a pro- tein misfolding cyclic amplification assay, which mimics the conversion process in vitro. We have used a modified version of this assay to inves- tigate the susceptibility of PrP^ expressed in the peripheral tissue of inbred mice to conversion to a protease resistant form, designated PrP—, in the presence of a seed of PrP^^ derived from a mouse adapted model of a hu- man TSE. This study identifies tissues that have the potential to act as reservoirs of infectivity and identifies routes of potential peripheral trans- mission of TSE disease.
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