Highly infectious prions are not directly neurotoxic

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 neu...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 117; no. 38; pp. 23815 - 23822
Main Authors Benilova, Iryna, Reilly, Madeleine, Terry, Cassandra, Wenborn, Adam, Schmidt, Christian, Marinho, Aline T., Risse, Emmanuel, Al-Doujaily, Huda, De Oliveira, Michael Wiggins, Sandberg, Malin K., Wadsworth, Jonathan D. F., Jat, Parmjit S., Collinge, John
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 22.09.2020
Subjects
Animals
Biological Sciences
Brain
Brain - cytology
Brain - drug effects
Brain Chemistry
Disease Models, Animal
Double-stranded
Fibers
Infectivity
Mice
Neurodegenerative diseases
Neurons - drug effects
Neurotoxicity
Neurotoxins - isolation & purification
Neurotoxins - metabolism
Neurotoxins - toxicity
Prion Diseases - metabolism
Prion Diseases - physiopathology
Prion protein
Prions
Prions - isolation & purification
Prions - metabolism
Prions - pathogenicity
Protein folding
Rodents
Toxicity
neurodegeneration
neurotoxicity
prions
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Summary: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.
Bibliography:Author contributions: I.B., M.R., P.S.J., and J.C. designed research; I.B., M.R., C.T., A.W., C.S., A.T.M., E.R., H.A.-D., and M.W.D.O. performed research; I.B., M.R., C.S., A.T.M., M.K.S., J.D.F.W., and J.C. analyzed data; and I.B., M.R., J.D.F.W., P.S.J., and J.C. wrote the paper.
2Present address: Molecular Systems for Health Research Group, School of Human Sciences, London Metropolitan University, London N7 8D, United Kingdom.
Edited by Reed B. Wickner, National Institutes of Health, Bethesda, MD, and approved August 10, 2020 (received for review April 20, 2020)
1I.B. and M.R. contributed equally to this work.
3P.S.J. and J.C. contributed equally to this work.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2007406117