Molecular distinction between pathogenic and infectious properties of the prion protein.
Tg(PG14) mice express a prion protein (PrP) with a nine-octapeptide insertion associated with a human familial prion disease. These animals spontaneously develop a fatal neurodegenerative disorder characterized by ataxia, neuronal apoptosis, and accumulation in the brain of an aggregated and weakly protease-resistant form of mutant PrP (designated PG14(spon)). Brain homogenates from Tg(PG14) mice fail to transmit disease after intracerebral inoculation into recipient mice, indicating that PG14(spon), although pathogenic, is distinct from PrP(Sc), the infectious form of PrP. In contrast, inoculation of Tg(PG14) mice with exogenous prions of the RML strain induces accumulation of PG14(RML), a PrP(Sc) form of the mutant protein that is infectious and highly protease resistant. Like PrP(Sc), both PG14(spon) and PG14(RML) display conformationally masked epitopes in the central and octapeptide repeat regions. However, these two forms differ profoundly in their oligomeric states, with PG14(RML) aggregates being much larger and more resistant to dissociation. Our analysis provides new molecular insight into an emerging puzzle in prion biology, the discrepancy between the infectious and neurotoxic properties of PrP.
Chiesa
Roberto
R
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Piccardo
Pedro
P
Quaglio
Elena
E
Drisaldi
Bettina
B
Si-Hoe
San Ling
SL
Takao
Masaki
M
Ghetti
Bernardino
B
Harris
David A
DA
D000818:Animals; D051379:Mice; D008822:Mice, Transgenic; D011328:Prions / Q000737:chemistry / Q000235:genetics / Q000472:pathogenicity*; D011487:Protein Conformation; D012608:Scrapie / Q000209:etiology
D011328:Prions