Highly infectious prions are not directly neurotoxic

Significance Prions are infectious agents composed of polymers of misfolded prion protein which cause fatal brain diseases such as Creutzfeldt–Jakob disease. These diseases involve progressive loss of neuronal cells, and it has been long assumed that prions are directly toxic to cells as they propagate. However, recent studies have suggested that prion infectivity and neurotoxicity can be uncoupled and involve distinct mechanisms. Using highly purified infectious prions we demonstrate that prions are not directly neurotoxic and that toxicity present in infected brain tissue can be distinguished from infectious prions. This has fundamental implications for understanding of prion diseases and how to treat them and may have wide relevance in other neurodegenerative diseases which involve propagation and spread of proteopathic seeds.
Prions are infectious agents which cause rapidly lethal neurodegenerative diseases in humans and animals following long, clinically silent incubation periods. They are composed of multichain assemblies of misfolded cellular prion protein. While it has long been assumed that prions are themselves neurotoxic, recent development of methods to obtain exceptionally pure prions from mouse brain with maintained strain characteristics, and in which defined structures—paired rod-like double helical fibers—can be definitively correlated with infectivity, allowed a direct test of this assertion. Here we report that while brain homogenates from symptomatic prion-infected mice are highly toxic to cultured neurons, exceptionally pure intact high-titer infectious prions are not directly neurotoxic. We further show that treatment of brain homogenates from prion-infected mice with sodium lauroylsarcosine destroys toxicity without diminishing infectivity. This is consistent with models in which prion propagation and toxicity can be mechanistically uncoupled.