title: Transgenic fatal familial insomnia mice indicate prion infectivity-independent mechanisms of pathogenesis and phenotypic expression of disease.
abstract: Fatal familial insomnia (FFI) and a genetic form of Creutzfeldt-Jakob disease (CJD178) are clinically different prion disorders linked to the D178N prion protein (PrP) mutation. The disease phenotype is determined by the 129 M/V polymorphism on the mutant allele, which is thought to influence D178N PrP misfolding, leading to the formation of distinctive prion strains with specific neurotoxic properties. However, the mechanism by which misfolded variants of mutant PrP cause different diseases is not known. We generated transgenic (Tg) mice expressing the mouse PrP homolog of the FFI mutation. These mice synthesize a misfolded form of mutant PrP in their brains and develop a neurological illness with severe sleep disruption, highly reminiscent of FFI and different from that of analogously generated Tg(CJD) mice modeling CJD178. No prion infectivity was detectable in Tg(FFI) and Tg(CJD) brains by bioassay or protein misfolding cyclic amplification, indicating that mutant PrP has disease-encoding properties that do not depend on its ability to propagate its misfolded conformation. Tg(FFI) and Tg(CJD) neurons have different patterns of intracellular PrP accumulation associated with distinct morphological abnormalities of the endoplasmic reticulum and Golgi, suggesting that mutation-specific alterations of secretory transport may contribute to the disease phenotype.
authors.affiliation: Department of Neuroscience, IRCCS-"Mario Negri" Institute for Pharmacological Research, Milan, Italy.
authors.forename: Ihssane
authors.initials: I
authors.lastname: Bouybayoune
authors.affiliation: Department of Neuroscience, IRCCS-"Mario Negri" Institute for Pharmacological Research, Milan, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Mantovani
authors.affiliation: Department of Health Sciences, University of Milan Medical School, Milan, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Del Gallo
authors.affiliation: Department of Neuroscience, IRCCS-"Mario Negri" Institute for Pharmacological Research, Milan, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bertani
authors.affiliation: Department of Neuroscience, IRCCS-"Mario Negri" Institute for Pharmacological Research, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Restelli
authors.affiliation: Department of Neuroscience, IRCCS-"Mario Negri" Institute for Pharmacological Research, Milan, Italy.
authors.forename: Liliana
authors.initials: L
authors.lastname: Comerio
authors.affiliation: Department of Neuroscience, IRCCS-"Mario Negri" Institute for Pharmacological Research, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Tapella
authors.affiliation: Department of Health Sciences, University of Milan Medical School, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Baracchi
authors.affiliation: CIC bioGUNE, Parque Tecnológico de Bizkaia, Derio, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Fernández-Borges
authors.affiliation: Division of Neuropathology and Neurology, IRCCS Foundation "Carlo Besta" National Neurological Institute, Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Mangieri
authors.affiliation: Bio-Imaging Unit, Department of Cardiovascular Research, IRCCS-"Mario Negri" Institute for Pharmacological Research, Milan, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Bisighini
authors.affiliation: IFOM-FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Galina V
authors.initials: GV
authors.lastname: Beznoussenko
authors.affiliation: Department of Neuroscience, IRCCS-"Mario Negri" Institute for Pharmacological Research, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Paladini
authors.affiliation: Department of Neuroscience, IRCCS-"Mario Negri" Institute for Pharmacological Research, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Balducci
authors.affiliation: Department of Neuroscience, IRCCS-"Mario Negri" Institute for Pharmacological Research, Milan, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Micotti
authors.affiliation: Department of Neuroscience, IRCCS-"Mario Negri" Institute for Pharmacological Research, Milan, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.affiliation: CIC bioGUNE, Parque Tecnológico de Bizkaia, Derio, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Castilla
authors.affiliation: Bio-Imaging Unit, Department of Cardiovascular Research, IRCCS-"Mario Negri" Institute for Pharmacological Research, Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Fiordaliso
authors.affiliation: Division of Neuropathology and Neurology, IRCCS Foundation "Carlo Besta" National Neurological Institute, Milan, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
authors.affiliation: Department of Health Sciences, University of Milan Medical School, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Imeri
authors.affiliation: Department of Neuroscience, IRCCS-"Mario Negri" Institute for Pharmacological Research, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Chiesa
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004569:Electroencephalography; D034062:Insomnia, Fatal Familial / Q000235:genetics* / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D010641:Phenotype; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics*
chemical_list: D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse