Disease relevance of Scrapie

• The normal cellular form of prion protein (PrPC) is a precursor to the pathogenic protease-resistant forms (PrPSc) believed to cause scrapie, bovine spongiform encephalopathy (BSE) and Creutzfeldt-Jakob disease [1].
• Recently, pathological prion protein PrP(Sc), the putative key constituent of infectious agents causing transmissible spongiform encephalopathies (TSEs), was found in muscles of rodents experimentally infected with scrapie and in patients with Creutzfeldt-Jakob disease (CJD) [2].
• It is suggested that the Carp (multiple-sclerosis associated and scrapie associated) agents may be the V-R.N.A. form of slow (D.N.A.) viruses which are the aetiological agents of the two diseases [3].
• Scrapie is a transmissible neurodegenerative disease that appears to result from an accumulation in the brain of an abnormal protease-resistant isoform of prion protein (PrP) called PrPsc [4].
• Exposure of susceptible neuroblastoma N2a cells to mouse scrapie prions leads to infection, as evidenced by the continued presence of the scrapie form of the prion protein (PrP(Sc)) and infectivity after 300 or more cell doublings [5].

Psychiatry related information on Scrapie

• The disease-specific amyloid fibrils comprise primarily a single protein, amyloid beta, in Alzheimer's disease, and the prion protein in scrapie [6].
• New-variant Creutzfeldt-Jakob disease and scrapie are typically initiated by extracerebral exposure to the causative agent, and exhibit early prion replication in lymphoid organs [7].
• These data suggest that both the noradrenergic and dopaminergic system are sensitive to the action of scrapie agent 87V and that changes in the catecholamine levels in the brains of scrapie-infected mice may contribute to some of the clinical symptoms of the diseases, such as ataxia and apraxia [8].

High impact information on Scrapie

• Models of amyloid seeding in Alzheimer's disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins [6].
• These results indicate that various PrP isoforms engage in a complex in vivo, whose distortion by PrP-Fc(2) affects prion propagation and scrapie pathogenesis [9].
• Classical genetic analysis has identified Sinc/Prni as the major gene controlling mouse scrapie incubation time [10].
• Similarly, Tg mice inoculated with Ha prions exhibited neuropathologic changes characteristic of hamsters with scrapie, while Mo prions produced changes similar to those in non-Tg mice [11].
• Tg 81 brains also showed HaPrP amyloid plaques characteristic of Ha scrapie and contained integral of 10(9) ID50 units of Ha prions based on Ha bioassays [12].

Chemical compound and disease context of Scrapie

• It was labeled with N-succinimidyl 3-(4-hydroxy-5-[125I]-iodophenyl) propionate, which did not alter the titer of the scrapie prion [13].
• Amphotericin B treatment dissociates in vivo replication of the scrapie agent from PrP accumulation [14].
• Chemical modification of the scrapie agent by diethyl pyrocarbonate reduced the titer 1000-fold [15].
• Autoclaving does not decontaminate formol-fixed scrapie tissues [16].
• This is a proteinase K-resistant glycoprotein of 27-30 kd that is derived from an abnormal isoform of a neuronal glycoprotein of 33-35 kd designated PrPSc and is a molecular marker of amyloid fibrils isolated from animals with scrapie and humans with related disorders [17].

Biological context of Scrapie

• Mice devoid of PrP develop normally but are resistant to scrapie; introduction of a PrP transgene restores susceptibility to the disease [18].
• A clone encoding PrP 27-30, the major protein in purified preparations of scrapie agent, was selected from a scrapie-infected hamster brain cDNA library by oligonucleotide probes corresponding to the N terminus of the protein [19].
• On the other hand, because there are many different strains of scrapie agent with distinct phenotypes which can be propagated in animals homozygous for the PrPc gene, it has been suggested that a nucleic acid must be a component of the agent [20].
• To study the effect of cell type-restricted hamster PrP expression on susceptibility to the hamster scrapie agent, we generated transgenic mice using a 1 kb hamster cDNA clone containing the 0.76 kb HPrP open reading frame under control of the neuron-specific enolase promoter [21].
• Species specificity in the cell-free conversion of prion protein to protease-resistant forms: a model for the scrapie species barrier [4].

Anatomical context of Scrapie

• Early PrPSc accumulation takes place on follicular dendritic cells (FDCs) within germinal centers in lymphoid tissues of patients with variant Creutzfeldt-Jakob disease (vCJD), sheep with natural scrapie or rodents following experimental peripheral infection with scrapie [22].
• Using these chimeric models, we obtained strong evidence that FDCs themselves produce PrP and that replication of a mouse-passaged scrapie strain in spleen depends on PrP-expressing FDCs rather than on lymphocytes or other bone marrow-derived cells [23].
• Instead, keratin 14-NGF transgenic mice, whose lymphoid organs are hyperinnervated by sympathetic nerves, showed reduction in scrapie incubation time and, unexpectedly, much higher titers of prion infectivity in spleens [24].
• Conversion of truncated and elongated prion proteins into the scrapie isoform in cultured cells [25].
• The apparent amphipathic character of the PrP 33-35Sc may explain the association of scrapie infectivity with both membranes and amyloid filaments [26].

Gene context of Scrapie

• After inoculation with hamster scrapie, these mice accumulated infectivity and PrPSc to high levels, developed severe disease after 227 +/- 5 days and died 7 +/- 4 days later [27].
• However, TNFR1(-/-), TNFR2(-/-), and some TNFalpha(-/-) mice developed scrapie similarly to wild-type mice [28].
• The results indicate that the accumulation of the scrapie prion protein in the CA1-3 region strongly inhibits NPY binding at the Y2-Rs, which, however, is only marginally due to reduced Y2-R mRNA expression [29].
• In scrapie, a prion disease of animals, amyloid plaques have been shown to be composed of prion proteins (PrP), which form filaments of relatively uniform diameter [30].
• In scrapie infected mice, cortical PV+ neurons were severely reduced while CB+ and CR+ neurons were well preserved [31].
• PrP(Sc) was clearly distinct from BSE prions passaged in sheep and from atypical scrapie prions [32].

Analytical, diagnostic and therapeutic context of Scrapie

• Seeding "one-dimensional crystallization" of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie [33]?
• Following intraperitoneal prion inoculation, chemical or immunological sympathectomy delayed or prevented scrapie [24].
• Molecular cloning and complete sequence of prion protein cDNA from mouse brain infected with the scrapie agent [34].
• Polyclonal antibodies produced against hamster scrapie amyloid protein (PrP27-30) and used in a neutralization test diminished infectivity of the PrPSc preparations by 1.6 log after intracerebral inoculation and by 1 log after intraperitoneal inoculation [35].
• Then confirmation must be sought by additional techniques such as PrP immunoblotting, preparations for electron microscopic examination of scrapie associated fibrils (SAF), molecular biologic studies, or experimental transmission [36].

References