Pathogenic Mutations within the Hydrophobic Domain of the Prion Protein Lead to the Formation of Protease-Sensitive Prion Species with Increased Lethality

Abstract

Prion diseases are a group of fatal and incurable neurodegenerative diseases affecting both humans and animals. The principal mechanism of these diseases involves the misfolding the host-encoded cellular prion protein, PrP C , into the disease-associated isoform, PrP Sc . Familial forms of human prion disease include those associated with the mutations G114V and A117V, which lie in the hydrophobic domain of PrP. Here we have studied the murine homologues (G113V and A116V) of these mutations using cell-based and animal models of prion infection. Under normal circumstances, the mutant forms of PrP C share similar processing, cellular localization, and physicochemical properties with wild-type mouse PrP (MoPrP). However, upon exposure of susceptible cell lines expressing these mutants to infectious prions, very low levels of protease-resistant aggregated PrP Sc are formed. Subsequent mouse bioassay revealed high levels of infectivity present in these cells. Thus, these mutations appear to limit the formation of aggregated PrP Sc , giving rise to the accumulation of a relatively soluble, protease sensitive, prion species that is highly neurotoxic. Given that these mutations lie next to the glycine-rich region of PrP that can abrogate prion infection, these findings provide further support for small, protease-sensitive prion species having a significant role in the progression of prion disease and that the hydrophobic domain is an important determinant of PrP conversion. IMPORTANCEPrion diseases are transmissible neurodegenerative diseases associated with an infectious agent called a prion. Prions are comprised of an abnormally folded form of the prion protein (PrP) that is normally resistant to enzymes called proteases. In humans, prion disease can occur in individuals who inherited mutations in the prion protein gene. Here we have studied the effects of two of these mutations and show that they influence the properties of the prions that can be formed. We show that the mutants make highly infectious prions that are more sensitive to protease treatment. This study highlights a certain region of the prion protein as being involved in this effect and demonstrates that prions are not always resistant to protease treatment.

Transmission of Soluble and Insoluble α-Synuclein to Mice

“…Furthermore, prion infectivity in rodents and sheep is associated with soluble components in the blood plasma, and soluble prions are detected in the blood of variant Creutzfeldt-Jakob patients (38-40). In addition, protease-sensitive prion diseases have been identified within the last decade, and pathogenic mutations of the prion protein lead to the formation of soluble, protease-sensitive prion species with increased lethality (41-44). In agreement with the prion field, our data suggest that both insoluble and soluble α-syn proteins from the brain of a LBD patient are transmissible under experimental conditions.…”

Human Prion Protein Conformational Changes Susceptibility: A Molecular Dynamics Simulation Study

“…It also has a palindromic sequence AGAAAAGAA that spans residues 113 to 120, as part of a downstream tightly packed hydrophobic core. Residues at positions 127 and 129 are polymorphic, as it could be either glycine or valine in the first case, and methionine or valine in the second one [7].…”

Modulation of prion polymerization and toxicity by rationally designed peptidomimetics

“…This conversion largely depends on interaction between the hydrophobic and aromatic residues in these helices [46][47][48]. Several reports indicate that such interactions indeed form the driving force in acquisition of protease-resistant core by prions and modulate their neurotoxicity [49][50][51].…”