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Assessing Transmissible Spongiform Encephalopathy Species Barriers with an In Vitro Prion Protein Conversion Assay
Published on: March 10, 2015
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Identification of a homology-independent linchpin domain controlling mouse and bank vole prion protein conversion
Cassandra M Burke1, Kenneth M K Mark1, Daniel J Walsh1
1Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
Plos Pathogens
|September 8, 2020
Summary
This study identifies key regions in prion protein (PrP) that influence its conversion into a pathogenic form (PrPSc). Specific amino acid residues and glycosylation patterns dictate susceptibility to prion templating, impacting neurodegenerative disease mechanisms.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Prions cause fatal neurodegenerative diseases by templating normal prion proteins (PrPC) into pathogenic forms (PrPSc).
- Understanding the molecular basis of PrPC to PrPSc conversion is crucial for developing therapeutic strategies against prion diseases.
Purpose of the Study:
- To identify the specific domains within bank vole and mouse PrPC that mediate conversion by a mouse protein-only recombinant PrPSc (recPrPSc).
- To investigate the role of amino acid residues E227 and S230, and N-linked glycosylation in prion templating.
Main Methods:
- Utilized chimeric bank vole/mouse PrPC substrates to assess conversion efficiency by mouse protein-only recPrPSc in vitro.
- Analyzed the impact of specific amino acid substitutions (E227, S230) and the presence/absence of the second N-linked glycan on prion conversion.
Main Results:
- The presence of bank vole residues E227 and S230, or the absence of the second N-linked glycan, were sufficient to enable conversion by mouse protein-only recPrPSc.
- These findings held true for several native infectious prion strains, indicating a conserved mechanism.
Conclusions:
- Bank vole amino acid residues 227 and 230, along with the second N-linked glycan status, form a critical C-terminal domain governing prion conversion.
- This domain acts as a linchpin, influencing susceptibility to prion templating across different species and prion strains.
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