General aspects of transmissible spongiform encephalopathies and hypotheses about the agents

This article reviews the shared characteristics of the group of transmissible spongiform encephalopathies (SEs), both human and animal, and the major theories regarding the nature of the agents involved. All transmissible SE diseases share two striking characteristics: the degenerative changes including vacuolation in the central nervous system, and the assumption that these disorders are caused by unconventional, transmissible agents. This article examines the major hypotheses that have been postulated about these agents: the virus theory, the virino theory, the prion theory, and the recently proposed 'unified theory'. Both the virus and the virino hypotheses assume that a small nucleic acid is involved as part of the agent, while the prion hypothesis does not. The prion model obviates the need for a role of a nucleic acid in the propagation and replication of the agent, but does not explain the existence of strain variation. Nucleic acids in a micro-organism, as proposed in the virino and the virus hypotheses, could explain this variation. However, to date, no disease-specific nucleic acids have been identified. The 'unified' theory tries to reconcile the essentials of the virino and prion theories. The article also describes the discovery of the so-called prion protein (PrP), its isoforms, and the coding host gene, the PrP gene. It goes on to discuss the results of experiments with transgenic animals, indicating that mutations in the PrP gene may play a decisive role in the pathogenesis of at least some SEs. Finally, two different models, both involving the conversion of normal PrPC into PrPSc as part of the pathogenesis of SE, are discussed.