Spontaneous generation of prion infectivity in fatal familial insomnia knock-in mice
Author(s)Faas, Henryk; Watson, Nicki; Borkowski, Andrew W.; Jasanoff, Alan Pradip; King, Oliver D.; Steele, Andrew D.; Lindquist, Susan; Jackson, Walker S.; ... Show more Show less
Spontaneous Generation of Prion Infectivity in Fatal Familial Insomnia Knockin Mice
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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.
DepartmentFrancis Bitter National Magnet Laboratory; 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
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.
Author's final manuscript