PRNP mutations initially generate an alternatively misfolded PrP species that dissuades prion replication

Mutations in the PRNP gene, responsible for producing the prion protein (PrP), can result in genetic prion disease. However, the connection between such mutations and the spontaneous formation of prions is not fully understood. By examining the role of BVPrP in mice, researchers aimed to uncover early events in prion formation. They observed that expressing mutated BVPrP versions, specifically D178N and E200K, in cells devoid of endogenous PrP led to the creation of an alternative misfolded PrP species, dubbed PrPAM.

This PrPAM is insoluble in detergents and resistant to digestion by the thermolysin enzyme. Notably, PrPAM is also detected in the brains of young mice that have been genetically engineered to express mutant BVPrP. Despite this, PrPAM does not seem to serve as a direct precursor for prion replication, as it does not respond to disease-protective genetic modifications, fails to be reduced by anti-prion drugs, resists infection from various prion strains, and does not contain seeds capable of inducing misfolding of the wild-type BVPrP in cells or the RT-QuIC assay.

These findings suggest that PRNP mutations responsible for genetic prion disease might first generate a protective misfolded PrP species that is impervious to prion formation, potentially explaining why these genetic diseases become apparent later in life, even though the mutations are inherited from birth.