Artificial strain of human prions created in vitro

Chae Kim, Xiangzhu Xiao, Shugui Chen, Tracy Haldiman, Vitautas Smirnovas, Diane Kofskey, Miriam Warren, Krystyna Surewicz, Nicholas R. Maurer, Qingzhong Kong, Witold Surewicz and Jiri G. Safar ()
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Chae Kim: Case Western Reserve University
Xiangzhu Xiao: Case Western Reserve University
Shugui Chen: Case Western Reserve University
Tracy Haldiman: Case Western Reserve University
Vitautas Smirnovas: Case Western Reserve University
Diane Kofskey: Case Western Reserve University
Miriam Warren: Case Western Reserve University
Krystyna Surewicz: Case Western Reserve University
Nicholas R. Maurer: Case Western Reserve University
Qingzhong Kong: Case Western Reserve University
Witold Surewicz: Case Western Reserve University
Jiri G. Safar: Case Western Reserve University

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract The molecular mechanism that determines under physiological conditions transmissibility of the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD) is unknown. We report the synthesis of new human prion from the recombinant human prion protein expressed in bacteria in reaction seeded with sCJD MM1 prions and cofactor, ganglioside GM1. These synthetic human prions were infectious to transgenic mice expressing non-glycosylated human prion protein, causing neurologic dysfunction after 459 and 224 days in the first and second passage, respectively. The neuropathology, replication potency, and biophysical profiling suggest that a novel, particularly neurotoxic human prion strain was created. Distinct biological and structural characteristics of our synthetic human prions suggest that subtle changes in the structural organization of critical domains, some linked to posttranslational modifications of the pathogenic prion protein (PrPSc), play a crucial role as a determinant of human prion infectivity, host range, and targetting of specific brain structures in mice models.

Date: 2018
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DOI: 10.1038/s41467-018-04584-z

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