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Assessing Transmissible Spongiform Encephalopathy Species Barriers with an In Vitro Prion Protein Conversion Assay
Published on: March 10, 2015
Quantifying the sequence-dependent species barrier between hamster and mouse prions
1Contribution from the Institute of Biological Chemistry, Academia Sinica, No. 128, Sec 2, Academia Road, Nankang, Taipei 115, Taiwan, Republic of China.
Abstract:
Prion diseases are transmissible neurodegenerative disorders. It is widely accepted that prions are the infectious agents responsible for disease transmission, and the sequence homology between the infectious prion and the host prion protein determines its transmission efficiency across species. However, previous studies have often reported different results regarding seeding efficiency, the efficiency of initiating amyloid propagation by adding pre-existing amyloid fibrils as seed. In the present study, we used synthetic peptides as a simple system to determine the sequence-dependent transmission barrier between hamster and mouse. We found that the heterologous seeding efficiency of hamster and mouse prion peptides was 4 times less than that of homologous seeding. Moreover, residue 139 was not the only residue in determining seeding efficiency. When the seed had Ile at this position, the homology at this position between seed and monomer determined the seeding efficiency. When the seed had Met at this position, homology at residues 109 and 112 determined the seeding efficiency.
Insights
Prion diseases involve sequence-dependent transmission barriers. This study reveals specific residues influencing prion seeding efficiency between hamster and mouse, impacting disease transmission dynamics.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Prion diseases are fatal, transmissible neurodegenerative disorders.
- Prion transmission efficiency across species is linked to sequence homology between infectious and host prion proteins.
- Seeding efficiency, crucial for prion propagation, has yielded inconsistent results in previous studies.
Purpose of the Study:
- To investigate the sequence-dependent transmission barrier between hamster and mouse prion peptides using a simplified synthetic system.
- To elucidate the specific amino acid residues that govern prion seeding efficiency and cross-species transmission.
Main Methods:
- Utilized synthetic peptides from hamster and mouse prion proteins to model cross-species transmission.
- Quantified heterologous and homologous seeding efficiency to assess transmission barriers.
- Analyzed the impact of specific residue variations (e.g., at position 139) on seeding efficiency.
Main Results:
- Heterologous seeding efficiency between hamster and mouse prion peptides was four times lower than homologous seeding.
- Residue 139 is not the sole determinant of seeding efficiency; its impact is context-dependent.
- When residue 139 was Ile, homology at that position governed seeding efficiency; when Met, residues 109 and 112 became critical.
Conclusions:
- Sequence homology plays a critical role in determining prion transmission barriers, even in simplified peptide systems.
- Specific amino acid residues and their interactions dictate prion seeding efficiency and cross-species transmission.
- Understanding these molecular determinants is key to comprehending prion disease pathogenesis and developing therapeutic strategies.
