Mutant Prion Protein Expression Causes Motor and Memory Deficits and Abnormal Sleep Patterns in a Transgenic Mouse Model

Sara Dossena, Luca Imeri, Michela Mangieri, Anna Garofoli, Loris Ferrari, Assunta Senatore, Elena Restelli, Claudia Balducci, Fabio Fiordaliso, Monica Salio, Susanna Bianchi, Luana Fioriti, Michela Morbin, Alessandro Pincherle, Gabriella Marcon, Flavio Villani, Mirjana Carli, Fabrizio Tagliavini, Gianluigi Forloni, Roberto Chiesa

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)598-609
Number of pages12
JournalNeuron
Volume60
Issue number4
DOIs
Publication statusPublished - Nov 26 2008

Keywords

  • CELLBIO
  • HUMDISEASE
  • SYSNEURO

ASJC Scopus subject areas

  • Neuroscience(all)

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