Mutant prion protein expression causes motor and memory deficits and abnormal sleep patterns in a transgenic mouse model.
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.
Dossena
Sara
S
Dulbecco Telethon Institute, 20156 Milan, Italy; Department of Neuroscience, "Mario Negri" Institute for Pharmacological Research, 20156 Milan, Italy.
Imeri
Luca
L
Mangieri
Michela
M
Garofoli
Anna
A
Ferrari
Loris
L
Senatore
Assunta
A
Restelli
Elena
E
Balducci
Claudia
C
Fiordaliso
Fabio
F
Salio
Monica
M
Bianchi
Susanna
S
Fioriti
Luana
L
Morbin
Michela
M
Pincherle
Alessandro
A
Marcon
Gabriella
G
Villani
Flavio
F
Carli
Mirjana
M
Tagliavini
Fabrizio
F
Forloni
Gianluigi
G
Chiesa
Roberto
R
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
D011328:Prions