Abstract
Prion diseases are driven by the strain-specific, template-dependent transconformation of the normal cellular prion protein (PrPC) into a disease specific isoform PrPSc. Cell culture models of prion infection generally use replicating cells resulting in lower levels of prion accumulation compared to animals. Using non-replicating cells allows the accumulation of higher levels of PrPSc and, thus, greater amounts of infectivity. Here, we infect non-proliferating muscle fiber myotube cultures prepared from differentiated myoblasts. We demonstrate that prion-infected myotubes generate substantial amounts of PrPSc and that the level of infectivity produced in these post-mitotic cells, 105.5 L.D.50/mg of total protein, approaches that observed in vivo. Exposure of the myotubes to different mouse-adapted agents demonstrates strain-specific replication of infectious agents. Mouse-derived myotubes could not be infected with hamster prions suggesting that the species barrier effect is intact. We suggest that non-proliferating myotubes will be a valuable model system for generating infectious prions and for screening compounds for anti-prion activity.
Highlights
Prions are the etiological agents responsible for the transmissible spongiform encephalopathies
Cell lines that divide rapidly tend not to support. This manuscript describes the generation of a new cell culture system to study the replication of infectious prions
While numerous cell lines exist that can replicate prions, these systems are usually based upon proliferating cells
Summary
Prions are the etiological agents responsible for the transmissible spongiform encephalopathies. These neurodegenerative diseases affect mammals, are inevitably fatal, and are always associated with the accumulation of a specific post-translationally modified isoform of a normal host glycoprotein, PrPC. This abnormal conformation, the PrPSc isoform, differs from PrPC structurally, resulting in dramatic functional consequences. In vivo the diseasespecific isoform of the prion protein (PrPSc) accumulates to high levels, a process that is marked by a progressive neurodegeneration that is always fatal as well as the generation of hundreds of millions of lethal doses of transmissible prions. Brain infectivity levels are extraordinarily high at clinical stage, 109 50% lethal doses (LD50) in end stage hamster brain and 108 LD50 in mouse models
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