Dissociation of prion protein amyloid seeding from transmission of a spongiform encephalopathy
ABSTRACT Misfolding and aggregation of proteins is a common pathogenic mechanism of a group of diseases called proteinopathies. The formation and spread of proteinaceous lesions within and between individuals was first described in prion diseases and proposed as the basis of its infectious nature. Recently a similar "prion-like" mechanism of transmission has been proposed in other neurodegenerative diseases such as Alzheimer's disease. We investigated if misfolding and aggregation of corrupted prion protein (PrP(TSE)) is always associated with horizontal transmission of disease. Knock-in transgenic mice (101LL) expressing mutant PrP (PrP-101L) that are susceptible to disease but do not develop any spontaneous neurological phenotype were inoculated with (i) brain extracts containing PrP(TSE) from healthy 101LL mice with PrP plaques in the corpus callosum or (ii) mice overexpressing PrP-101L with neurological disease, severe spongiform encephalopathy and formation of proteinase-K-resistant PrP(TSE). In all instances, 101LL mice developed PrP plaques in the area of inoculation and vicinity in the absence of clinical disease or spongiform degeneration of the brain. Importantly 101LL mice did not transmit disease on serial passage ruling out the presence of subclinical infection. Thus, in both experimental models formation of PrP(TSE) is not infectious. These results have implications for the interpretation of tests based on the detection of protein aggregates and suggest that de novo formation of PrP(TSE) in the host does not always result in a transmissible prion disease. In addition, these results question the validity of assuming that all diseases due to protein misfolding can be transmitted between individuals.
Full-textDOI: · Available from: Rona Barron, Apr 27, 2015
- SourceAvailable from: John Hopkins
[Show abstract] [Hide abstract]
- "In some scrapie strain/host combinations high titres of infectivity are associated with low levels of PrP Sc (Barron et al., 2007); in others the accumulation of PrP Sc in the brain is not associated with transmissible disease (Piccardo et al., 2013). This lack of direct correlation between quantitative levels of PrP Sc aggregation and infectivity raises two major questions. "
ABSTRACT: Sheep scrapie is a transmissible spongiform encephalopathy (TSE), progressive and fatal neurodegenerative diseases of the central nervous system (CNS) linked to the accumulation of misfolded prion protein, PrPSc. New Zealand Cheviot sheep, homozygous for the VRQ genotype of the PRNP gene are most susceptible with an incubation period of 193 days with SSBP/1 scrapie. However, the earliest time point that PrPSc can be detected in the CNS is 125 days (D125). The aim of this study was to quantify changes to the transcriptome of the thalamus and obex (medulla) at times immediately before (D75) and after (D125) PrPSc was detected. Affymetrix gene arrays were used to quantify gene expression in the thalamus and Illumina DGE-tag profiling for obex. Ingenuity Pathway Analysis was used to help describe the biological processes of scrapie pathology. Neurological disease and Cancer were common Bio Functions in each tissue at D75; inflammation and cell death were major processes at D125. Several neurological receptors were significantly increased at D75 (e.g. CHRNA6, GRM1, HCN2), which might be clues to the molecular basis of psychiatric changes associated with TSEs. No genes were significantly differentially expressed at both D75 and D125 and there was no progression of events from earlier to later time points. This implies that there is no simple linear progression of pathological or molecular events. There seems to be a step-change between D75 and D125, correlating with the detection of PrPSc, resulting in the involvement of different pathological processes in later TSE diseaseVeterinary Microbiology 10/2014; 173(3-4). DOI:10.1016/j.vetmic.2014.07.026 · 2.73 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Variably protease-sensitive prionopathy (VPSPr) can occur in persons of all codon 129 genotypes in the human prion protein gene (PRNP) and is characterized by a unique biochemical profile when compared with other human prion diseases. We investigated transmission properties of VPSPr by inoculating transgenic mice expressing human PRNP with brain tissue from 2 persons with the valine-homozygous (VV) and 1 with the heterozygous methionine/valine codon 129 genotype. No clinical signs or vacuolar pathology were observed in any inoculated mice. Small deposits of prion protein accumulated in the brains of inoculated mice after challenge with brain material from VV VPSPr patients. Some of these deposits resembled microplaques that occur in the brains of VPSPr patients. Comparison of these transmission properties with those of sporadic Creutzfeldt-Jakob disease in the same lines of mice indicated that VPSPr has distinct biological properties. Moreover, we established that VPSPr has limited potential for human-to-human transmission.Emerging infectious diseases 12/2014; 20(12):1969-79. DOI:10.3201/eid2012.140214 · 7.33 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: 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 (PrP(C)). 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 PrP(C) is not an efficient conversion substrate (or mouse brain not a favorable environment) and therefore cannot sustain replication beyond the first passage.Emerging infectious diseases 12/2014; 20(12):2006-14. DOI:10.3201/eid2012.140548 · 7.33 Impact Factor