Spontaneous generation of prion infectivity in fatal familial insomnia knock-in mice
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Author(s)
Faas, Henryk
Watson, Nicki
Borkowski, Andrew W.
Jasanoff, Alan Pradip
King, Oliver D.
Steele, Andrew D.
Lindquist, Susan
Jackson, Walker S.
Alternative Title
Spontaneous Generation of Prion Infectivity in Fatal Familial Insomnia Knockin Mice
Date Issued
August 2009
Journal
Neuron
Publisher
Elsevier Inc.
Citation
Jackson W.S., Borkowski A.W., Faas H., Steele A.D., King O.D., Watson N., Jasanoff A., Lindquist S. Spontaneous Generation of Prion Infectivity in Fatal Familial Insomnia Knockin Mice (2009) Neuron, 63 (4), pp. 438-450.
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Author's final manuscript
Abstract
A crucial tenet of the prion hypothesis is that misfolding of the prion protein (PrP) induced by mutations associated with familial prion disease is, in an otherwise normal mammalian brain, sufficient to generate the infectious agent. Yet this has never been demonstrated. We engineered knockin mice to express a PrP mutation associated with a distinct human prion disease, fatal familial insomnia (FFI). An additional substitution created a strong transmission barrier against pre-existing prions. The mice spontaneously developed a disease distinct from that of other mouse prion models and highly reminiscent of FFI. Unique pathology was transmitted from FFI mice to mice expressing wild-type PrP sharing the same transmission barrier. FFI mice were highly resistant to infection by pre-existing prions, confirming infectivity did not arise from contaminating agents. Thus, a single amino acid change in PrP is sufficient to induce a distinct neurodegenerative disease and the spontaneous generation of prion infectivity.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Massachusetts Institute of Technology. Department of Nuclear Science and Engineering
Whitehead Institute for Biomedical Research
Francis Bitter Magnet Laboratory (Massachusetts Institute of Technology)
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1016/j.neuron.2009.07.026
