Unknown

Dataset Information

0

Destabilizing polymorphism in cervid prion protein hydrophobic core determines prion conformation and conversion efficiency.


ABSTRACT: Prion diseases are infectious neurodegenerative disorders of humans and animals caused by misfolded forms of the cellular prion protein PrPC. Prions cause disease by converting PrPC into aggregation-prone PrPSc. Chronic wasting disease (CWD) is the most contagious prion disease with substantial lateral transmission, affecting free-ranging and farmed cervids. Although the PrP primary structure is highly conserved among cervids, the disease phenotype can be modulated by species-specific polymorphisms in the prion protein gene. How the resulting amino-acid substitutions impact PrPC and PrPSc structure and propagation is poorly understood. We investigated the effects of the cervid 116A>G substitution, located in the most conserved PrP domain, on PrPC structure and conversion and on 116AG-prion conformation and infectivity. Molecular dynamics simulations revealed structural de-stabilization of 116G-PrP, which enhanced its in vitro conversion efficiency when used as recombinant PrP substrate in real-time quaking-induced conversion (RT-QuIC). We demonstrate that 116AG-prions are conformationally less stable, show lower activity as a seed in RT-QuIC and exhibit reduced infectivity in vitro and in vivo. Infectivity of 116AG-prions was significantly enhanced upon secondary passage in mice, yet conformational features were retained. These findings indicate that structurally de-stabilized PrPC is readily convertible by cervid prions of different genetic background and results in a prion conformation adaptable to cervid wild-type PrP. Conformation is an important criterion when assessing transmission barrier, and conformational variants can target a different host range. Therefore, a thorough analysis of CWD isolates and re-assessment of species-barriers is important in order to fully exclude a zoonotic potential of CWD.

SUBMITTER: Hannaoui S 

PROVIDER: S-EPMC5568445 | BioStudies | 2017-01-01

REPOSITORIES: biostudies

Similar Datasets

2020-01-01 | S-EPMC6946595 | BioStudies
2019-01-01 | S-EPMC6901582 | BioStudies
2016-01-01 | S-EPMC5102397 | BioStudies
1000-01-01 | S-EPMC5585258 | BioStudies
| S-EPMC4097672 | BioStudies
2019-01-01 | S-EPMC6673760 | BioStudies
2019-01-01 | S-EPMC6882122 | BioStudies
2017-01-01 | S-EPMC5589181 | BioStudies
2013-01-01 | S-EPMC3839929 | BioStudies
2015-01-01 | S-EPMC4665243 | BioStudies