title: Mutant prion protein expression causes motor and memory deficits and abnormal sleep patterns in a transgenic mouse model.
abstract: A familial form of Creutzfeldt-Jakob disease (CJD) is linked to the D178N/V129 prion protein (PrP) mutation. Tg(CJD) mice expressing the mouse homolog of this mutant PrP synthesize a misfolded form of the mutant protein, which is aggregated and protease resistant. These mice develop clinical and pathological features reminiscent of CJD, including motor dysfunction, memory impairment, cerebral PrP deposition, and gliosis. Tg(CJD) mice also display electroencephalographic abnormalities and severe alterations of sleep-wake patterns strikingly similar to those seen in a human patient carrying the D178N/V129 mutation. Neurons in these mice show swelling of the endoplasmic reticulum (ER) with intracellular retention of mutant PrP, suggesting that ER dysfunction could contribute to the pathology. These results establish a transgenic animal model of a genetic prion disease recapitulating cognitive, motor, and neurophysiological abnormalities of the human disorder. Tg(CJD) mice have the potential for giving greater insight into the spectrum of neuronal dysfunction in prion diseases.
authors.affiliation: Dulbecco Telethon Institute, 20156 Milan, Italy; Department of Neuroscience, "Mario Negri" Institute for Pharmacological Research, 20156 Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Dossena
authors.forename: Luca
authors.initials: L
authors.lastname: Imeri
authors.forename: Michela
authors.initials: M
authors.lastname: Mangieri
authors.forename: Anna
authors.initials: A
authors.lastname: Garofoli
authors.forename: Loris
authors.initials: L
authors.lastname: Ferrari
authors.forename: Assunta
authors.initials: A
authors.lastname: Senatore
authors.forename: Elena
authors.initials: E
authors.lastname: Restelli
authors.forename: Claudia
authors.initials: C
authors.lastname: Balducci
authors.forename: Fabio
authors.initials: F
authors.lastname: Fiordaliso
authors.forename: Monica
authors.initials: M
authors.lastname: Salio
authors.forename: Susanna
authors.initials: S
authors.lastname: Bianchi
authors.forename: Luana
authors.initials: L
authors.lastname: Fioriti
authors.forename: Michela
authors.initials: M
authors.lastname: Morbin
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pincherle
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marcon
authors.forename: Flavio
authors.initials: F
authors.lastname: Villani
authors.forename: Mirjana
authors.initials: M
authors.lastname: Carli
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.forename: Roberto
authors.initials: R
authors.lastname: Chiesa
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007562:Creutzfeldt-Jakob Syndrome / Q000150:complications* / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D004569:Electroencephalography; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D004734:Energy Metabolism / Q000235:genetics; D005071:Evoked Potentials / Q000235:genetics; D008569:Memory Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009069:Movement Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D011328:Prions / Q000235:genetics*; D012893:Sleep Wake Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D011328:Prions