Strain-Specific Targeting and Destruction of Cells by Prions.

Simple Summary: Prions are novel infectious agents that consist only of protein. It is known that in the same host species, different strains of prion can occur that differ by the cells that are infected and killed. The mechanism responsible for these observations is only beginning to be understood. Two main ideas, which are not mutually exclusive, may provide a framework to understand strain targeting. The first possibility is that as prions spread throughout the CNS they reach strain-specific populations of cells that trigger cell death. The second mechanism is that prions exist in two distinct forms, a replicative form that switches to the production of a toxic form that results in the destruction of cells and the eventual onset of clinical signs of disease. Both neurons and glia may participate in both of these possibilities. The relative contributions of each mechanism have yet to be determined. Prion diseases are caused by the disease-specific self-templating infectious conformation of the host-encoded prion protein, PrP^Sc. Prion strains are operationally defined as a heritable phenotype of disease under controlled conditions. One of the hallmark phenotypes of prion strain diversity is tropism within and between tissues. A defining feature of prion strains is the regional distribution of PrP^Sc in the CNS. Additionally, in both natural and experimental prion disease, stark differences in the tropism of prions in secondary lymphoreticular system tissues occur. The mechanism underlying prion tropism is unknown; however, several possible hypotheses have been proposed. Clinical target areas are prion strain-specific populations of neurons within the CNS that are susceptible to neurodegeneration following the replication of prions past a toxic threshold. Alternatively, the switch from a replicative to toxic form of PrP^Sc may drive prion tropism. The normal form of the prion protein, PrP^C, is required for prion formation. More recent evidence suggests that it can mediate prion and prion-like disease neurodegeneration. In vitro systems for prion formation have indicated that cellular cofactors contribute to prion formation. Since these cofactors can be strain specific, this has led to the hypothesis that the distribution of prion formation cofactors can influence prion tropism. Overall, there is evidence to support several mechanisms of prion strain tropism; however, a unified theory has yet to emerge. [ABSTRACT FROM AUTHOR]