Mutant prion protein expression causes motor and memory deficits and abnormal sleep patterns in a transgenic mouse model
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Published on: April 13, 2017
Sara Dossena1, Luca Imeri, Michela Mangieri
1Dulbecco Telethon Institute, 20156 Milan, Italy; Department of Neuroscience, "Mario Negri" Institute for Pharmacological Research, 20156 Milan, Italy.
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.
Insights
A new transgenic mouse model replicates familial Creutzfeldt-Jakob disease (CJD) symptoms, including cognitive and motor deficits. These mice exhibit prion protein aggregation and endoplasmic reticulum dysfunction, offering insights into genetic prion diseases.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Familial Creutzfeldt-Jakob disease (CJD) is associated with the D178N/V129 prion protein (PrP) mutation.
- Understanding the molecular mechanisms of genetic prion diseases is crucial for developing therapeutic strategies.
Purpose of the Study:
- To establish a transgenic mouse model that recapitulates the key features of familial CJD.
- To investigate the role of misfolded prion protein and endoplasmic reticulum dysfunction in CJD pathogenesis.
Main Methods:
- Generation of transgenic (Tg(CJD)) mice expressing the D178N/V129 mutant mouse prion protein homolog.
- Characterization of clinical, pathological, electrophysiological, and sleep-wake pattern abnormalities in Tg(CJD) mice.
- Histopathological analysis of neuronal endoplasmic reticulum structure and prion protein deposition.
Main Results:
- Tg(CJD) mice exhibit motor and memory impairments, cerebral PrP deposition, and gliosis, mirroring human CJD.
- These mice display electroencephalographic abnormalities and altered sleep patterns similar to human patients with the D178N/V129 mutation.
- Neuronal swelling of the endoplasmic reticulum and intracellular retention of mutant PrP suggest ER dysfunction contributes to pathology.
Conclusions:
- Tg(CJD) mice serve as a valuable animal model for genetic prion diseases, accurately reflecting human cognitive, motor, and neurophysiological deficits.
- This model provides a platform for further research into the neuronal dysfunction spectrum in prion diseases and potential therapeutic interventions.
