Artificial strain of human prions created in vitro.
Chae KimXiangzhu XiaoShugui ChenTracy HaldimanVitautas SmirnovasDiane KofskeyMiriam WarrenKrystyna SurewiczNicholas R MaurerQingzhong KongWitold K SurewiczJiri G SafarPublished in: Nature communications (2018)
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.
Keyphrases
- endothelial cells
- induced pluripotent stem cells
- pluripotent stem cells
- type diabetes
- oxidative stress
- multiple sclerosis
- metabolic syndrome
- skeletal muscle
- high resolution
- recombinant human
- blood brain barrier
- small molecule
- functional connectivity
- resting state
- white matter
- early onset
- protein protein
- electron transfer