Artificial strain of human prions created in vitro

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

Variable Protease-Sensitive Prionopathy Transmission to Bank Voles

Variably protease-sensitive prionopathy (VPSPr), a recently described human sporadic prion disease, features a protease-resistant, disease-related prion protein (resPrPD) displaying 5 fragments reminiscent of Gerstmann-Sträussler-Scheinker disease. Experimental VPSPr transmission to human PrP–expressing transgenic mice, although replication of the VPSPr resPrPD profile succeeded, has been incomplete because of second passage failure. We bioassayed VPSPr in bank voles, which are susceptible to human prion strains. Transmission was complete; first-passage attack rates were 5%–35%, and second-passage rates reached 100% and survival times were 50% shorter. We observed 3 distinct phenotypes and resPrPD profiles; 2 imitated sporadic Creutzfeldt-Jakob disease resPrPD, and 1 resembled Gerstmann-Sträussler-Scheinker disease resPrPD. The first 2 phenotypes may be related to the presence of minor PrPD components in VPSPr. Full VPSPr transmission confirms permissiveness of bank voles to human prions and suggests that bank vole PrP may efficiently reveal an underrepresented native strain but does not replicate the complex VPSPr PrPD profile

Transmission Characteristics of Variably Protease-Sensitive Prionopathy

Variably protease-sensitive prionopathy (VPSPr), a recently identified and seemingly sporadic human prion disease, is distinct from Creutzfeldt-Jakob disease (CJD) but shares features of Gerstmann-Sträussler-Scheinker disease (GSS). However, contrary to exclusively inherited GSS, no prion protein (PrP) gene variations have been detected in VPSPr, suggesting that VPSPr might be the long-sought sporadic form of GSS. The VPSPr atypical features raised the issue of transmissibility, a prototypical property of prion diseases. We inoculated VPSPr brain homogenate into transgenic mice expressing various levels of human PrP (PrPC). On first passage, 54% of challenged mice showed histopathologic lesions, and 34% harbored abnormal PrP similar to that of VPSPr. Surprisingly, no prion disease was detected on second passage. We concluded that VPSPr is transmissible; thus, it is an authentic prion disease. However, we speculate that normal human PrPC is not an efficient conversion substrate (or mouse brain not a favorable environment) and therefore cannot sustain replication beyond the first passage

Cité internationale

juin 19881988/06

Prion Protein Protects against Renal Ischemia/Reperfusion Injury.

The cellular prion protein (PrPC), a protein most noted for its link to prion diseases, has been found to play a protective role in ischemic brain injury. To investigate the role of PrPC in the kidney, an organ highly prone to ischemia/reperfusion (IR) injury, we examined wild-type (WT) and PrPC knockout (KO) mice that were subjected to 30-min of renal ischemia followed by 1, 2, or 3 days of reperfusion. Renal dysfunction and structural damage was more severe in KO than in WT mice. While PrP was undetectable in KO kidneys, Western blotting revealed an increase in PrP in IR-injured WT kidneys compared to sham-treated kidneys. Compared to WT, KO kidneys exhibited increases in oxidative stress markers heme oxygenase-1, nitrotyrosine, and Nε-(carboxymethyl)lysine, and decreases in mitochondrial complexes I and III. Notably, phosphorylated extracellular signal-regulated kinase (pERK) staining was predominantly observed in tubular cells from KO mice following 2 days of reperfusion, a time at which significant differences in renal dysfunction, histological changes, oxidative stress, and mitochondrial complexes between WT and KO mice were observed. Our study provides the first evidence that PrPC may play a protective role in renal IR injury, likely through its effects on mitochondria and ERK signaling pathways

Additional file 6: Figure S4. of Iatrogenic Creutzfeldt-Jakob disease with Amyloid-β pathology: an international study

Quantitative estimates of Thioflavin S-positive Aβ CP affecting the cerebral cortex in subjects with iCJD and sporadic AD (sAD). A: the density of Aβ CP, expressed as the percentage of cerebral cortex area occupied, was 5 times greater in subjects with sAD than in iCJD. B: size of Aβ CP (N=500), expressed as diameter, was greater in patients with sAD than in those with iCJD. C and D: representative microscopic fields showing fewer and smaller CP (arrows) in iCJD (C) than sAD (D) where cluster of very large CP (dashed square) could be detected. Bar graphs are expressed as mean ± standard error of the mean (SEM) in A or as mean ± standard deviation in B. Student's t-test (two-tailed). (PDF 3338 kb

Additional file 7: Figure S5. of Iatrogenic Creutzfeldt-Jakob disease with Amyloid-β pathology: an international study

Size of blood vessels examined and semiquantitative evaluation of the percentage of the vessel wall perimeters occupied by Aβ deposits in subjects with iCJD and sporadic AD (sAD). A: scatter plot showing the similar sizes of the blood vessels from the subarachnoid spaces of frontal, occipital and cerebellar regions examined for the semiquantitative determinations made in B; size of individual vessels is measured as perimeter. B: the percentage of the blood vessel wall occupied by Aβ was significantly greater in iCJD than sAD. Bar graphs are expressed as mean±SEM. Student's t-test (two-tailed). (PDF 228 kb