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Benilova, Iryna, Reilly, Madeleine, Terry, Cassandra, Wenborn, Adam, Schmidt, Christian, Marinho, Aline T., Risse, Emmanuel, Al-Doujaily, Huda, Wiggins De Oliveira, Michael, Sandberga, Malin K., Wadsworth, Jonathan D. F., Jat, Parmjit S and Collinge, John (2020) Highly infectious prions are not directly neurotoxic. Proceedings of the National Academy of Sciences (PNAS). pp. 1-8. ISSN 0027-8424
Prions are infectious agents which cause rapidly lethal neurode- generative diseases in humans and animals following long, clini- cally 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 devel- opment 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 fur- ther show that treatment of brain homogenates from prion-infected mice with sodium lauroylsarcosine destroys toxicity without diminish- ing infectivity. This is consistent with models in which prion propa- gation and toxicity can be mechanistically uncoupled.
Available under License Creative Commons Attribution 4.0.
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