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Updated: May 23, 2026
Protein Misfolding Cyclic Amplification of Prions
Published on: November 7, 2012
Identification of I137M and other mutations that modulate incubation periods for two human prion strains
Kurt Giles1, Gian Felice De Nicola, Smita Patel
1Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, California, USA.
Abstract:
We report here the transmission of human prions to 18 new transgenic (Tg) mouse lines expressing 8 unique chimeric human/mouse prion proteins (PrP). Extracts from brains of two patients, who died of sporadic Creutzfeldt-Jakob disease (sCJD), contained either sCJD(MM1) or sCJD(VV2) prion strains and were used for inocula. Mice expressing chimeric PrP showed a direct correlation between expression level and incubation period for sCJD(MM1) prions irrespective of whether the transgene encoded methionine (M) or valine (V) at polymorphic residue 129. Tg mice expressing chimeric transgenes encoding V129 were unexpectedly resistant to infection with sCJD(VV2) prions, and when transmission did occur, it was accompanied by a change in strain type. The transmission of sCJD(MM1) prions was modulated by single amino acid reversions of each human PrP residue in the chimeric sequence. Reverting human residue 137 in the chimeric transgene from I to M prolonged the incubation time for sCJD(MM1) prions by more than 100 days; structural analyses suggest a profound change in the orientation of amino acid side chains with the I→M mutation. These findings argue that changing the surface charge in this region of PrP greatly altered the interaction between PrP isoforms during prion replication. Our studies contend that strain-specified replication of prions is modulated by PrP sequence-specific interactions between the prion precursor PrP(C) and the infectious product PrP(Sc).
Insights
Human prion transmission to transgenic mice reveals that prion strain replication depends on specific interactions between prion protein isoforms. Mouse models demonstrate how prion protein sequence affects disease incubation and strain type.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal neurodegenerative disorder caused by prions.
- Understanding prion strain diversity and transmission is crucial for developing diagnostics and therapeutics.
Purpose of the Study:
- To investigate the role of prion protein (PrP) sequence in human prion transmission and strain propagation.
- To develop and utilize transgenic mouse models for studying sCJD.
Main Methods:
- Transmission of sCJD(MM1) and sCJD(VV2) prion strains to 18 transgenic mouse lines expressing chimeric human/mouse PrP.
- Analysis of incubation periods, prion strain typing, and structural changes in response to PrP sequence variations.
Main Results:
- Chimeric PrP expression levels correlated with incubation periods for sCJD(MM1) prions.
- Mice expressing V129 chimeric PrP showed resistance to sCJD(VV2) prions, with altered strain types upon transmission.
- A single amino acid reversion (I→M at residue 137) significantly prolonged incubation for sCJD(MM1) prions, altering PrP structure and interactions.
Conclusions:
- Prion replication and strain characteristics are modulated by specific interactions between prion protein (PrP) isoforms.
- PrP sequence, particularly surface charge, significantly influences prion-host interactions and disease progression.
- Transgenic mouse models provide valuable insights into the molecular mechanisms of prion disease pathogenesis.
