Genetic and infectious prion diseases
S. B. Prusiner
Department of Neurology, University of California, San Francisco.
Enriching fractions from Syrian hamster (SHa) brain for scrapie prion
infectivity led to the discovery of the prion protein (PrP). Prion diseases
include scrapie of sheep and bovine spongiform encephalopathy of cattle as
well as Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Scheinker
syndrome (GSS) of humans. Transgenic (Tg) mice expressing both SHa and
mouse (Mo) PrP genes were used to probe the molecular basis of the species
barrier and the mechanism of scrapie prion replication. Bioassays of brain
extracts from two scrapie-infected Tg lines showed that the prion inoculum
determines that prions are synthesized de novo, even though the cells
express both PrP genes. Studies with artificial prions produced from
chimeric Mo/SHaPrP transgenes underscore the concept that inoculated prion
dictates which prion will be replicated. Discovery of mutations in the PrP
genes of humans with GSS and familial CJD established that prion diseases
are both genetic and infectious. Transgenic mice expressing high levels of
MoPrP-P101L, corresponding to the GSS point mutation (P102L) in human PrP,
spontaneously develop neurologic dysfunction, spongiform degeneration, and
astrocytic gliosis. Inoculation of brain extracts prepared from these Tg
(MoPrP-P101L) mice produced neurodegeneration in recipient animals after
prolonged incubation times. These results are in accord with those of other
studies and argue that prions are devoid of foreign nucleic acid.
Structural investigations of cellular prion protein (PrPC) and prion
protein scrapie (PrPSc) suggest that the difference may be conformational.
Conditions that diminished the beta-sheet content of PrPSc were the same as
those identified previously that inactivate prion infectivity. Whether
prion diversity as reflected by distinct "strains" producing different
patterns of PrPSc accumulation is due to different conformers of PrPSc
remains to be established. Advances in the purification and
characterization of both PrPC and PrPSc seem to have identified the central
event in PrPSc synthesis and prion propagation, ie, the unfolding of PrPC
followed by its refolding into PrPSc. These findings underscore the
fundamental features of prion structure and propagation that differentiate
prions from other transmissible pathogens.
Microglial Cell Line Established from Prion Protein-Overexpressing Mice Is Susceptible to Various Murine Prion Strains
Iwamaru et al.
J. Virol. 2007;81:1524-1527.
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Horse madness (hippomania) and hippophobia.
Papakostas et al.
History of Psychiatry 2005;16:467-471.
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Presenile dementia syndromes: an update on taxonomy and diagnosis
Greicius et al.
J. Neurol. Neurosurg. Psychiatry 2002;72:691-700.
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Ultrasensitive detection of pathological prion protein aggregates by dual-color scanning for intensely fluorescent targets
Bieschke et al.
Proc. Natl. Acad. Sci. USA 2000;97:5468-5473.
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Risk of Transmission of Bovine Spongiform Encephalopathy to Humans in the United States: Report of the Council on Scientific Affairs
Tan et al.
JAMA 1999;281:2330-2339.
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Marked decrease of neuropeptide Y Y2 receptor binding sites in the hippocampus in murine prion disease
Diez et al.
Proc. Natl. Acad. Sci. USA 1997;94:13267-13272.
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Commentary Review: Prion Diseases
Shetty and Steele
CLIN PEDIATR 1997;36:1-7.
Apolipoprotein E: Emerging Story in the Pathogenesis of Alzheimer's Disease
Strittmatter and Roses
Neuroscientist 1995;1:298-306.
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