J. Neurochem. (2011) 119, 251–261.
Prions, the agents responsible for transmissible spongiform encephalopathies, are infectious proteins consisting primarily of scrapie prion protein (PrPSc), a misfolded, β-sheet enriched and aggregated form of the host-encoded cellular prion protein (PrPC). Their propagation is based on an autocatalytic PrP conversion process. Despite the lack of a nucleic acid genome, different prion strains have been isolated from animal diseases. Increasing evidence supports the view that strain-specific properties may be enciphered within conformational variations of PrPSc. In humans, sporadic Creutzfeldt-Jakob disease (sCJD) is the most frequent form of prion diseases and has demonstrated a wide phenotypic and molecular spectrum. In contrast, variant Creutzfeldt-Jakob disease (vCJD), which results from oral exposure to the agent of bovine spongiform encephalopathy, is a highly stereotyped disease, that, until now, has only occurred in patients who are methionine homozygous at codon 129 of the PrP gene. Recent research has provided consistent evidence of strain diversity in sCJD and also, unexpectedly enough, in vCJD. Here, we discuss the puzzling biochemical/pathological diversity of human prion disorders and the relationship of that diversity to the biological properties of the agent as demonstrated by strain typing in experimental models.
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"In CGN Hu cultures that expressed human PrP with a methionine or a valine at codon 129, we propagated 4 different CJD isolates (iCJD MM1 , vCJD MM2b , and sCJD MM1 in CGN Hu-Met129 ; sCJD VV2a in CGN Hu-Val129 ). It has been demonstrated that the agents involved in sCJD MM1 , sCJD VV2a , and vCJD MM2b are distinct prion strains[2,13]. We observed a significant effect of cycline treatment in infected CGN cultures that varies with the CJD isolate and the studied compound. "
[Show abstract][Hide abstract]ABSTRACT: In prion diseases, a major issue in therapeutic research is the variability of the effect between strains. Stimulated by the
report of an antiprion effect in a scrapie model and by ongoing international clinical trials using doxycycline, we studied
the efficacy of cyclines against the propagation of human prions. First, we successfully propagated various Creutzfeldt-Jakob
disease (CJD) isolates (sporadic, variant, and iatrogenic CJD) in neuronal cultures expressing the human prion protein. Then,
we found that doxycycline was the most effective compound, with important variations between isolates. Isolates from sporadic
CJD, the most common form of prion disease, showed the highest sensitivity.
Full-text · Article · Nov 2013 · The Journal of Infectious Diseases
"Apoptotic neurons in CJD are probably related to the presence of inflammatory cells and cytokines which are present during the whole CJD disease process . Lack of or very limited activated microglia in the CNS tissues of FFI and G114 gCJD suggest that recruitment of inflammatory cells is not the major reason for neuronal destruction for these two inherited prion diseases, which highlight again the diversity of the pathogenesis of human prion diseases [1,27]. "
[Show abstract][Hide abstract]ABSTRACT: Microglial activations have been described in different subtypes of human prion diseases such as sporadic Creutzfeldt-Jakob disease (CJD), variant CJD, Kuru and Gerstmann-Straussler-Scheinker disease (GSS). However, the situation of microglia in other genetic prion diseases such as fatal familial insomnia (FFI) and familial CJD remains less understood. The brain microglia was evaluated comparatively between the FFI, G114V and sCJD cases in the study.
Specific Western blots, immunohistochemical and immunofluorescent assays were used to detect the changes of microglia and ELISA tests were used for levels of inflammatory cytokines.
Western blots, immunohistochemical and immunofluorescent assays illustrated almost unchanged microglia in the temporal lobes of FFI and G114V gCJD, but obviously increased in those of sCJD. The Iba1-levels maintained comparable in six different brain regions of FFI and G114V cases, including thalamus, cingulate gyrus, frontal cortex, parietal cortex, occipital cortex and temporal cortex. ELISA tests for inflammatory cytokines revealed significantly up-regulated IL-1beta, IL-6 and TNF-alpha in the brain homogenates from sCJD, but not in those from FFI and G114V gCJD.
Data here demonstrates silent brain microglia in FFI and G114V gCJD but obviously increased in sCJD, which reflects various pathogenesis of different human prion diseases subtypes.
"In elk, one epidemiological study suggested that animals with a leucine at codon 132 may be resistant to infection with the CWD agent, whereas those with methionine are susceptible , although this could not be confirmed in experimentally infectedelk . The codon 132 polymorphism is particularly intriguing, given that all patients suffering from vCJD to date are homozygous for methionine at the analogous codon 129 of the human Prnp gene [40,41]. The reason for this genetic resistance or enhanced susceptibility has yet to be explained, but may relate to either the conformation or expression level of native PrP C in these individuals. "