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Molecular distinction between pathogenic and infectious properties of the prion protein
Roberto Chiesa1, Pedro Piccardo, Elena Quaglio
1Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Abstract:
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.
Insights
Tg(PG14) mice develop neurodegenerative disease from mutant prion protein (PrP) aggregates. These aggregates are pathogenic but not infectious, unlike PrP(Sc), highlighting a key difference in prion biology.
Area of Science:
- Neuroscience
- Molecular Biology
- Prion Biology
Background:
- Tg(PG14) mice express a mutant prion protein (PrP) linked to familial human prion disease.
- These mice spontaneously develop a fatal neurodegenerative disorder.
Purpose of the Study:
- To investigate the properties of spontaneously occurring mutant PrP aggregates (PG14(spon)) versus infectious PrP aggregates (PG14(RML)) in Tg(PG14) mice.
- To understand the discrepancy between prion infectivity and neurotoxicity.
Main Methods:
- Intracerebral inoculation of Tg(PG14) mice with RML strain prions.
- Biochemical analysis of mutant PrP aggregates (PG14(spon) and PG14(RML)).
- Conformational and oligomeric state analysis of PrP aggregates.
Main Results:
- Spontaneous PG14(spon) aggregates are pathogenic but not transmissible, distinct from infectious PrP(Sc).
- RML prion inoculation induces infectious and protease-resistant PG14(RML) aggregates in Tg(PG14) mice.
- PG14(spon) and PG14(RML) differ significantly in their oligomeric size and stability, despite sharing masked epitopes.
Conclusions:
- Mutant PrP can form distinct pathogenic and infectious aggregates with differing properties.
- The study provides molecular insights into the divergence of prion infectivity and neurotoxicity.
- This research clarifies the complex behavior of mutant prion proteins in neurodegenerative disease models.