Prion diseases: current understanding of epidemiology and pathogenesis, and therapeutic advances.

CEA-National TSE Reference Laboratory, Istituto Zooprofilattico Sperimentale del Piemonte, Turin, Italy.
CNS Drugs (Impact Factor: 5.11). 02/2006; 20(1):15-28.
Source: PubMed


The bovine spongiform encephalopathy (BSE) epidemic, along with the related threat to human health posed by the transmission of the BSE agent to humans, has highlighted the importance of prion diseases. These fatal neurodegenerative diseases are characterised by spongiform changes in the CNS, and comprise a wide spectrum of clinicopathological entities in humans and animals, such as Creutzfeldt-Jakob disease (CJD) and its emerging new variant (vCJD) in humans, and BSE and scrapie in animals. This article reviews the geographical distribution and the temporal trends of CJD and vCJD; the major events in the pathogenesis of prion diseases; the risk factors for sporadic CJD and vCJD; and the possible strategies for treating them. Worldwide statistics indicate that sporadic CJD has a stable incidence of one case per million people per year; in contrast, the incidence of vCJD appears to have increased exponentially from its characterisation in 1994 to a peak in 2000. As of December 2005, 183 definite or probable cases of vCJD had been reported worldwide. The crucial event in the pathogenesis of prion diseases is the conversion of the normally occurring cellular prion protein (PrP(c)) into a pathogenic form, called protease-resistant PrP (PrP(res)) or scrapie PrP (PrP(sc)). Pathogenetic studies in rodent models have shown that PrP(sc) is found in the enteric nervous system and in the gut-associated lymphoid tissue following oral scrapie ingestion. The role of the lymphoreticular system in the pathogenesis of TSE seems to be related to the strains of agents and the host genotype. Therapeutic approaches to vCJD are mainly based on the inhibition or prevention of the pathological change that creates PrP(sc). Derivatives of acridine (such as mepacrine [quinacrine]) and the phenothiazine psychotropics have been proposed as possible therapies because of their activity in cellular models; however, neither class was able to affect the protease resistance of preexisting PrP fibrils. More encouragingly, in animal models of prion disease, tetracyclines were found to reduce prion infectivity by direct inactivation of PrP(sc). While these findings are promising, the suitability of these compounds for clinical use is still limited by their low efficacy once symptoms are apparent. Treatments based on the vaccination approach have also produced positive results, but further investigations are necessary to establish their clinical application.


Available from: Giuseppe Ru, Jul 15, 2014
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    • "The two acridine derivatives studied in this work for their anti-TBSV effects are CPZ and QC with known anti-prion [28], [36], [37], [38], [39], [40], anti-Alzheimer's beta-amyloid fibril formation [41], anti-malaria [42], anti-Bacillus anthracis toxin [43] and anti-cancer activities [44], [45]. Additional documented effects of CPZ include inhibition of the formation of clathrin-coated pits and the relocation of clathrin and clathrin-associated adaptor complex AP2 from the cell surface, which is critical for clathrin-mediated endocytosis used by severe acute respiratory syndrome coronavirus (SARS-CoV), dengue virus 2, Crimean-Congo hemorrhagic fever virus, vesicular stomatitis virus, HIV, mouse hepatitis virus type 2 during cell entry [46], [47], [48], [49], [50], [51], [52]. "
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    ABSTRACT: Small molecule inhibitors of RNA virus replication are potent antiviral drugs and useful to dissect selected steps in the replication process. To identify antiviral compounds against Tomato bushy stunt virus (TBSV), a model positive stranded RNA virus, we tested acridine derivatives, such as chlorpromazine (CPZ) and quinacrine (QC), which are active against prion-based diseases. Here, we report that CPZ and QC compounds inhibited TBSV RNA accumulation in plants and in protoplasts. In vitro assays revealed that the inhibitory effects of these compounds were manifested at different steps of TBSV replication. QC was shown to have an effect on multiple steps, including: (i) inhibition of the selective binding of the p33 replication protein to the viral RNA template, which is required for recruitment of viral RNA for replication; (ii) reduction of minus-strand synthesis by the tombusvirus replicase; and (iii) inhibition of translation of the uncapped TBSV genomic RNA. In contrast, CPZ was shown to inhibit the in vitro assembly of the TBSV replicase, likely due to binding of CPZ to intracellular membranes, which are important for RNA virus replication. Since we found that CPZ was also an effective inhibitor of other plant viruses, including Tobacco mosaic virus and Turnip crinkle virus, it seems likely that CPZ has a broad range of antiviral activity. Thus, these inhibitors constitute effective tools to study similarities in replication strategies of various RNA viruses.
    PLoS ONE 10/2009; 4(10):e7376. DOI:10.1371/journal.pone.0007376 · 3.23 Impact Factor
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    • "Methods (2009), doi:10.1016/j.mimet.2009.01.017 varies depending on the nature of the infective strain, the route of transmission, and the genetic susceptibility of the recipient. This has led to the fear that an unknown proportion of the population who have been eating potentially contaminated meat in the 1980s might currently present as asymptomatic carriers of the vCJD infectious agent, despite current statistics which indicate that the number of deaths by vCJD peaked in 2000 and has been in decline since (Caramelli et al., 2006; Setbon et al., 2005). Beside transmission of the infectious agent through the ingestion of contaminated products, bearing in mind the potential threat of vCJD incubating in the population, a number of medical procedures are now also considered as posing a potential risk of iatrogenic contamination with PrP Sc (Pana and Jung, 2005; Lumley and Serious Hazards of Transfusion Committee, 2008). "
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    ABSTRACT: Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases with no cure to this day, and are often associated with the accumulation of amyloid plaques in the brain and other tissues in affected individuals. The emergence of new variant Creutzfeldt-Jakob disease, an acquired TSE with a relatively long asymptomatic incubation period and unknown prevalence or incidence, which could potentially be iatrogenically transmitted, has prompted the need for sensitive and rapid methods of detection of the pathology indicator, the protease-resistant prion protein (PrP(Sc)), in tissues and on surgical instruments. To discriminate between common tissue proteins and amyloid-rich aggregates such as those formed by abnormal prion, we developed a quantitative thioflavin T/SYPRO Ruby dual staining procedure, used in combination with episcopic differential interference contrast/epifluorescence (EDIC/EF) microscopy for rapid scanning of samples. The detection limit of this direct observation technique applied to brain homogenates was greatly enhanced by the addition of Tween 20, as demonstrated in double-blind studies using various proportions of ME7-infected brain mixed with normal brain homogenate. The characteristic thioflavin T signal correlated with the relative amount of prion amyloid and proved at least 2-log more sensitive than the classic Western blot using the same prepared samples. This new sensitive microscopy procedure, which can be easily applied in instrument decontamination surveys, is likely to be more sensitive that Western blot in practice since it does not rely on the elution of resilient PrP(Sc) bound to the instrument surfaces. Our study also demonstrates how interactions between prion and lipid-rich tissue homogenates may reduce the sensitivity of such detection assays.
    Journal of microbiological methods 02/2009; 77(1):90-7. DOI:10.1016/j.mimet.2009.01.017 · 2.03 Impact Factor
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    • "At this time, the epidemiological evidence suggest that among animal TSEs only cattle BSE has been transmitted to humans, generating a variant form of CJD (vCJD) (Bruce, 2000; Collinge, 1999; Ironside and Head, 2004). It is unlikely that sheep scrapie is a concern for humans, because the disease has been described for centuries and no increased prevalence of human prion diseases has been found in scrapie endemic areas (Caramelli et al., 2006; Hunter, 1998). However, the appearance on new " atypical " strains of scrapie as well as the known transmission of BSE to sheep has generated new concerns of human infections with sheep-derived material (Buschmann and Groschup, 2005; Hunter, 2003). "
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    ABSTRACT: Prions are unconventional infectious agents composed exclusively of misfolded prion protein (PrP(Sc)), which transmits the disease by propagating its abnormal conformation to the cellular prion protein (PrP(C)). A key characteristic of prions is their species barrier, by which prions from one species can only infect a limited number of other species. Here, we report the generation of infectious prions by interspecies transmission of PrP(Sc) misfolding by in vitro PMCA amplification. Hamster PrP(C) misfolded by mixing with mouse PrP(Sc) generated unique prions that were infectious to wild-type hamsters, and similar results were obtained in the opposite direction. Successive rounds of PMCA amplification result in adaptation of the in vitro-produced prions, in a process reminiscent of strain stabilization observed upon serial passage in vivo. Our results indicate that PMCA is a valuable tool for the investigation of cross-species transmission and suggest that species barrier and strain generation are determined by the propagation of PrP misfolding.
    Cell 10/2008; 134(5):757-68. DOI:10.1016/j.cell.2008.07.030 · 32.24 Impact Factor
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