Spontaneous generation of prions and transmissible PrP amyloid in a humanised transgenic mouse model of A117V GSS.

Inherited prion diseases are caused by autosomal dominant coding mutations in the human prion protein (PrP) gene (PRNP) and account for about 15% of human prion disease cases worldwide. The proposed mechanism is that the mutation predisposes to conformational change in the expressed protein, leading to the generation of disease-related multichain PrP assemblies that propagate by seeded protein misfolding. Despite considerable experimental support for this hypothesis, to-date spontaneous formation of disease-relevant, transmissible PrP assemblies in transgenic models expressing only mutant human PrP has not been demonstrated.

Transmission Properties of Human PrP 102L Prions Challenge the Relevance of Mouse Models of GSS.

Inherited prion disease (IPD) is caused by autosomal-dominant pathogenic mutations in the human prion protein (PrP) gene (PRNP). A proline to leucine substitution at PrP residue 102 (P102L) is classically associated with Gerstmann-Sträussler-Scheinker (GSS) disease but shows marked clinical and neuropathological variability within kindreds that may be caused by variable propagation of distinct prion strains generated from either PrP 102L or wild type PrP. To-date the transmission properties of prions propagated in P102L patients remain ill-defined.

A naturally occurring variant of the human prion protein completely prevents prion disease.

Mammalian prions, transmissible agents causing lethal neurodegenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP). A novel PrP variant, G127V, was under positive evolutionary selection during the epidemic of kuru--an acquired prion disease epidemic of the Fore population in Papua New Guinea--and appeared to provide strong protection against disease in the heterozygous state. Here we have investigated the protective role of this variant and its interaction with the common, worldwide M129V PrP polymorphism.

Inherited prion disease A117V is not simply a proteinopathy but produces prions transmissible to transgenic mice expressing homologous prion protein.

Prions are infectious agents causing fatal neurodegenerative diseases of humans and animals. In humans, these have sporadic, acquired and inherited aetiologies. The inherited prion diseases are caused by one of over 30 coding mutations in the human prion protein (PrP) gene (PRNP) and many of these generate infectious prions as evidenced by their experimental transmissibility by inoculation to laboratory animals.