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Updated: Mar 29, 2026
High-throughput Screening for Protein-based Inheritance in S. cerevisiae
Published on: August 8, 2017
Mutated but Not Deleted Ovine PrP(C) N-Terminal Polybasic Region Strongly Interferes with Prion Propagation in
Manal Khalifé1, Fabienne Reine2, Sophie Paquet-Fifield2
1UMR1313 Génétique Animale et Biologie Intégrative, Institut National de la Recherche Agronomique, Jouy-en-Josas, France.
Unlabelled:
Mammalian prions are proteinaceous infectious agents composed of misfolded assemblies of the host-encoded, cellular prion protein (PrP). Physiologically, the N-terminal polybasic region of residues 23 to 31 of PrP has been shown to be involved in its endocytic trafficking and interactions with glycosaminoglycans or putative ectodomains of membrane-associated proteins. Several recent reports also describe this PrP region as important for the toxicity of mutant prion proteins and the efficiency of prion propagation, both in vitro and in vivo. The question remains as to whether the latter observations made with mouse PrP and mouse prions would be relevant to other PrP species/prion strain combinations given the dramatic impact on prion susceptibility of minimal amino acid substitutions and structural variations in PrP. Here, we report that transgenic mouse lines expressing ovine PrP with a deletion of residues 23 to 26 (KKRP) or mutated in this N-terminal region (KQHPH instead of KKRPK) exhibited a variable, strain-dependent susceptibility to prion infection with regard to the proportion of affected mice and disease tempo relative to findings in their wild-type counterparts. Deletion has no major effect on 127S scrapie prion pathogenesis, whereas mutation increased by almost 3-fold the survival time of the mice. Deletion marginally affected the incubation time of scrapie LA19K and ovine bovine spongiform encephalopathy (BSE) prions, whereas mutation caused apparent resistance to disease.
Importance:
Recent reports suggested that the N-terminal polybasic region of the prion protein could be a therapeutic target to prevent prion propagation or toxic signaling associated with more common neurodegenerative diseases such as Alzheimer's disease. Mutating or deleting this region in ovine PrP completes the data previously obtained with the mouse protein by identifying the key amino acid residues involved.
Insights
Altering the N-terminal region of ovine prion protein (PrP) affects susceptibility to prion diseases. Specific mutations significantly increased survival time and conferred resistance, highlighting this region as a potential therapeutic target.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Mammalian prions are infectious proteins causing neurodegenerative diseases.
- The N-terminal polybasic region (residues 23-31) of prion protein (PrP) is implicated in trafficking, interactions, and prion propagation.
- Previous studies in mice suggested this region's importance, but its relevance in other PrP species remained unclear.
Purpose of the Study:
- To investigate the role of the N-terminal polybasic region of ovine prion protein (PrP) in prion disease susceptibility.
- To determine if mutations or deletions in this region impact prion pathogenesis and disease tempo in transgenic mice.
- To assess the therapeutic potential of targeting this PrP region for neurodegenerative diseases.
Main Methods:
- Generated transgenic mouse lines expressing ovine PrP with specific N-terminal modifications (deletion of residues 23-26 or mutation to KQHPH).
- Inoculated these mice with different prion strains (127S scrapie, LA19K scrapie, ovine BSE).
- Monitored disease progression, survival times, and susceptibility compared to wild-type controls.
Main Results:
- Deletion of residues 23-26 (KKRP) had minimal impact on 127S scrapie pathogenesis.
- Mutation of the N-terminal region (to KQHPH) increased survival time by nearly threefold for one prion strain.
- This mutation also conferred apparent resistance to ovine BSE and marginally affected incubation time for LA19K scrapie.
Conclusions:
- The N-terminal polybasic region of ovine PrP plays a critical, strain-dependent role in prion susceptibility.
- Specific amino acid alterations in this region can significantly modulate disease progression and confer resistance.
- Targeting the N-terminal PrP region represents a promising therapeutic strategy for prion and potentially other neurodegenerative diseases.
