Rapidly progressive dementia with thalamic degeneration and peculiar cortical prion protein immunoreactivity, but absence of proteinase K resistant PrP: a new disease entity?

ABSTRACT In the transmissible spongiform encephalopathies, disease is closely associated with the conversion of the normal proteinase K-sensitive host prion protein (PrP-sen) to the abnormal proteinase K-resistant form (PrP-res). Amino acid sequence homology between PrP-res and PrP-sen is important in the formation of new PrP-res and thus in the efficient transmission of infectivity across species barriers. It was previously shown that the generation of mouse PrP-res was strongly influenced by homology between PrP-sen and PrP-res at amino acid residue 138, a residue located in a region of loop structure common to PrP molecules from many different species. In order to determine if homology at residue 138 also affected the formation of PrP-res in a different animal species, we assayed the ability of hamster PrP-res to convert a panel of recombinant PrP-sen molecules to protease-resistant PrP in a cell-free conversion system. Homology at amino acid residue 138 was not critical for the formation of protease-resistant hamster PrP. Rather, homology between PrP-sen and hamster PrP-res at amino acid residue 155 determined the efficiency of formation of a protease-resistant product induced by hamster PrP-res. Structurally, residue 155 resides in a turn at the end of the first alpha helix in hamster PrP-sen; this feature is not present in mouse PrP-sen. Thus, our data suggest that PrP-res molecules isolated from scrapie-infected brains of different animal species have different PrP-sen structural requirements for the efficient formation of protease-resistant PrP.

Download Full-text

Prion protein immunoreactivity in brain samples from an unselected autopsy population: findings in 200 consecutive cases

Neuropathology and Applied Neurobiology ◽

10.1046/j.1365-2990.2000.00239.x ◽

2000 ◽

Vol 26 (3) ◽

pp. 273-284 ◽

Cited By ~ 39

Author(s):

M. M. Esiri ◽

J. Carter ◽

J. W. Ironside

Keyword(s):

Prion Protein ◽

Protein Immunoreactivity

Download Full-text

Genetic human prion disease modelled in PrP transgenic Drosophila

Biochemical Journal ◽

10.1042/bcj20170462 ◽

2017 ◽

Vol 474 (19) ◽

pp. 3253-3267 ◽

Cited By ~ 3

Author(s):

Alana M. Thackray ◽

Alzbeta Cardova ◽

Hanna Wolf ◽

Lydia Pradl ◽

Ina Vorberg ◽

...

Keyword(s):

Prion Protein ◽

Prion Disease ◽

Prion Diseases ◽

Principal Component ◽

Site Directed Mutagenesis ◽

Host Protein ◽

Therapeutic Interventions ◽

Proteinase K ◽

Human Prion Disease ◽

Transgenic Drosophila

Inherited human prion diseases, such as fatal familial insomnia (FFI) and familial Creutzfeldt–Jakob disease (fCJD), are associated with autosomal dominant mutations in the human prion protein gene PRNP and accumulation of PrPSc, an abnormal isomer of the normal host protein PrPC, in the brain of affected individuals. PrPSc is the principal component of the transmissible neurotoxic prion agent. It is important to identify molecular pathways and cellular processes that regulate prion formation and prion-induced neurotoxicity. This will allow identification of possible therapeutic interventions for individuals with, or at risk from, genetic human prion disease. Increasingly, Drosophila has been used to model human neurodegenerative disease. An important unanswered question is whether genetic prion disease with concomitant spontaneous prion formation can be modelled in Drosophila. We have used pUAST/PhiC31-mediated site-directed mutagenesis to generate Drosophila transgenic for murine or hamster PrP (prion protein) that carry single-codon mutations associated with genetic human prion disease. Mouse or hamster PrP harbouring an FFI (D178N) or fCJD (E200K) mutation showed mild Proteinase K resistance when expressed in Drosophila. Adult Drosophila transgenic for FFI or fCJD variants of mouse or hamster PrP displayed a spontaneous decline in locomotor ability that increased in severity as the flies aged. Significantly, this mutant PrP-mediated neurotoxic fly phenotype was transferable to recipient Drosophila that expressed the wild-type form of the transgene. Collectively, our novel data are indicative of the spontaneous formation of a PrP-dependent neurotoxic phenotype in FFI- or CJD-PrP transgenic Drosophila and show that inherited human prion disease can be modelled in this invertebrate host.

Download Full-text

Mitral valve prolapse is not a new disease entity

The American Journal of Cardiology ◽

10.1016/0002-9149(88)90682-0 ◽

1988 ◽

Vol 62 (9) ◽

pp. 660 ◽

Cited By ~ 1

Author(s):

Tsung O. Cheng

Keyword(s):

Mitral Valve ◽

Mitral Valve Prolapse ◽

New Disease ◽

Disease Entity

Download Full-text

Orthorexia nervosa – a new disease entity associated with dysfunctional eating patterns

Medycyna Ogólna i Nauki o Zdrowiu ◽

10.26444/monz/122257 ◽

2020 ◽

Vol 26 (2) ◽

pp. 102-105

Author(s):

Michalina Mróz ◽

Emilia Korek

Keyword(s):

Orthorexia Nervosa ◽

Eating Patterns ◽

New Disease ◽

Disease Entity

Download Full-text

Effect of Non-Concentrated and Concentrated Vaporized Hydrogen Peroxide on Scrapie Prions

Pathogens ◽

10.3390/pathogens9110947 ◽

2020 ◽

Vol 9 (11) ◽

pp. 947

Author(s):

Akikazu Sakudo ◽

Risa Yamashiro ◽

Chihiro Harata

Keyword(s):

Hydrogen Peroxide ◽

Prion Protein ◽

Protein Misfolding ◽

Soft Mode ◽

Brain Homogenate ◽

Proteinase K ◽

Mouse Bioassay ◽

Half Cycle ◽

Cover Glass ◽

Standard Mode

To date, there have been no studies on the sterilization of prions by non-concentrated and concentrated vaporized hydrogen peroxide (VHP) applied by the same instrument. Here, the effect of the two types of VHP applied using an ES-700 sterilizer on prions was investigated. Brain homogenate from scrapie (Chandler) prion-infected mice was spotted on a cover glass and subjected to ES-700 treatment in soft (non-concentrated VHP from 59% hydrogen peroxide) or standard (concentrated VHP from 80% hydrogen peroxide) mode. Proteinase K-resistant prion protein (PrPres), an indicator of the abnormal isoform of prion protein (PrPSc), was reduced by ES-700 treatment under several conditions: SFT1/4 (soft mode, quarter cycle), SFT1/2 (soft mode, half cycle), SFT1 (soft mode, full cycle), and STD1/2 (standard mode, half cycle). PrPres was detected after the first and second rounds of protein misfolding cyclic amplification (PMCA) of untreated samples, but was undetectable in SFT1/4, SFT1/2, SFT1, and STD1/2 treated samples. In a mouse bioassay, SFT1/2 and STD1/2 treatment of prions significantly prolonged survival time, suggesting that prion infectivity is reduced after ES-700 treatment. In summary, both non-concentrated and concentrated VHP inactivate prions and may be useful for the low-temperature sterilization of prion-contaminated medical devices.

Download Full-text

Synergistic and strain-specific effects of bovine spongiform encephalopathy and scrapie prions in the cell-free conversion of recombinant prion protein

Journal of General Virology ◽

10.1099/vir.0.81590-0 ◽

2006 ◽

Vol 87 (12) ◽

pp. 3753-3761 ◽

Cited By ~ 13

Author(s):

Martin Eiden ◽

Gottfried J. Palm ◽

Winfried Hinrichs ◽

Ulrich Matthey ◽

Ralph Zahn ◽

...

Keyword(s):

Bovine Spongiform Encephalopathy ◽

Prion Protein ◽

De Novo ◽

Proteinase K ◽

Spongiform Encephalopathy ◽

Cooperative Action ◽

Specific Effects ◽

Scrapie Strains ◽

Recombinant Prion Protein

This study describes the conversion of murine PrPC by PrPSc from three different mouse scrapie strains (ME7, 87V and 22A) and from a mouse-passaged bovine spongiform encephalopathy (BSE) strain (BSE/Bl6). This was demonstrated by a modified, non-radioactive, cell-free conversion assay using bacterial prion protein, which was converted into a proteinase K (PK)-resistant fragment designated PrPres. Using this assay, newly formed PrPres could be detected by an antibody that discriminated de novo PrPres and the original PrPSc seed. The results suggested that PrPres formation occurs in three phases: the first 48 h when PrPres formation is delayed, followed by a period of substantially accelerated PrPres formation and a plateau phase when a maximum concentration of PrPres is reached after 72 h. The conversion of prokaryotically expressed PrPC by ME7 and BSE prions led to unglycosylated, PK-digested, abnormal PrPres fragments, which differed in molecular mass by 1 kDa. Therefore, prion strain phenotypes were retained in the cell-free conversion, even when recombinant PrPC was used as the substrate. Moreover, co-incubation of ME7 and BSE prions resulted in equal amounts of both ME7- and BSE-derived PrPres fragments (as distinguished by their different molecular sizes) and also in a significantly increased total amount of de novo-generated PrPres. This was found to be more than twice the amount of either strain when incubated separately. This result indicates a synergistic effect of both strains during cell-free conversion. It is not yet known whether such a cooperative action between BSE and scrapie prions also occurs in vivo.

Download Full-text