title: Transgenic mice recapitulate the phenotypic heterogeneity of genetic prion diseases without developing prion infectivity: Role of intracellular PrP retention in neurotoxicity.
abstract: Genetic prion diseases are degenerative brain disorders caused by mutations in the gene encoding the prion protein (PrP). Different PrP mutations cause different diseases, including Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome and fatal familial insomnia (FFI). The reason for this variability is not known. It has been suggested that prion strains with unique self-replicating and neurotoxic properties emerge spontaneously in individuals carrying PrP mutations, dictating the phenotypic expression of disease. We generated transgenic mice expressing the FFI mutation, and found that they developed a fatal neurological illness highly reminiscent of FFI, and different from those of similarly generated mice modeling genetic CJD and GSS. Thus transgenic mice recapitulate the phenotypic differences seen in humans. The mutant PrPs expressed in these mice are misfolded but unable to self-replicate. They accumulate in different compartments of the neuronal secretory pathway, impairing the membrane delivery of ion channels essential for neuronal function. Our results indicate that conversion of mutant PrP into an infectious isoform is not required for pathogenesis, and suggest that the phenotypic variability may be due to different effects of mutant PrP on intracellular transport.
authors: a Laboratory of Prion Neurobiology, Department of Neuroscience, IRCCS - "Mario Negri" Institute for Pharmacological Research , Milan , Italy;
authors: Roberto
authors: R
authors: Chiesa
authors: a Laboratory of Prion Neurobiology, Department of Neuroscience, IRCCS - "Mario Negri" Institute for Pharmacological Research , Milan , Italy;
authors: Elena
authors: E
authors: Restelli
authors: a Laboratory of Prion Neurobiology, Department of Neuroscience, IRCCS - "Mario Negri" Institute for Pharmacological Research , Milan , Italy;
authors: Liliana
authors: L
authors: Comerio
authors: b Department of Health Sciences , University of Milan Medical School , Milan , Italy.
authors: Federico
authors: F
authors: Del Gallo
authors: b Department of Health Sciences , University of Milan Medical School , Milan , Italy.
authors: Luca
authors: L
authors: Imeri
mesh_terms: D000818:Animals; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics / Q000473:pathology; D016098:Gerstmann-Straussler-Scheinker Disease / Q000235:genetics / Q000473:pathology; D006801:Humans; D034062:Insomnia, Fatal Familial / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D017096:Prion Diseases / Q000235:genetics* / Q000473:pathology; D000072002:Prion Proteins / Q000032:analysis / Q000235:genetics*; D017510:Protein Folding; D012756:Sheep
chemical_list: D000072002:Prion Proteins
keywords: Creutzfeldt-Jakob disease; Genetic prion disease; Gerstmann-Sträussler-Scheinker syndrome; PrPC; PrPSc; fatal familial insomnia; membrane trafficking; protein misfolding; sleep; transgenic mice