Creutzfeldt-Jakob disease (CJD) is a degenerative brain disease caused by prions, infectious agents that are made of misfolded proteins (the correct folding of a protein is essential for its function). In CJD, prions cause normal proteins to refold into a diseased state. This happens slowly at first, but normal proteins in the brain are converted at an ever-increasing rate, in a kind of feedback loop. The diseased proteins disrupt normal cell functioning and ultimately cause cell death, creating 'holes' in the tissue.
CJD is always fatal, and infects approximately one in a million people a year worldwide. Prion diseases affect many different species, as the prion protein is similar in all mammals. Bovine spongiform encephalopathy ('mad cow disease') is perhaps the best known of these.
One of the problems prion researchers face when using animal models to study CJD is that prion diseases in humans have a more complex range of clinical signs than can be seen in mice. Humans experience dementia and other disturbances that don't affect movement, whereas in mice only motor dysfunctions, which occur at a late stage of the disease, have been seen.
In the current study, researchers looked at a prion protein mutation (named D178N/V129) that is associated with a kind of CJD in which patients suffer memory deterioration, behavioural changes and motor abnormalities. The only mouse models available were of mice bred with an inherited form of CJD, and these mice did not show any of the same cognitive impairments suffered by their human counterparts.
Dr Roberto Chiesa of the Mario Negri Institute for Pharmacological Research in Italy explained, "We need experimental models with a broader spectrum of clinical signs for insight into the mechanisms of neuronal dysfunction and its evolution, and to identify earlier markers of clinical disease when therapeutic intervention may be effective."
The scientists were able to permanently transfer the relevant defective gene into a mouse's genetic material, such that the mouse expressed its own version of the D178N/V129 mutation. The result was an animal that exhibited similar symptoms to human CJD patients. The animals, called Tg(CJD) mice, show memory impairment and neurophysiologic deficits, including electroencephalography (EEG) abnormalities and sleep alterations, similar to those experienced by a CJD patient with the same mutation.
The researchers also observed other biological abnormalities in the Tg(CJD) mice that suggest that alterations in the endoplasmic reticulum (a part of the cell responsible for protein folding) might contribute to CJD pathology.
"Our results establish the first animal model of a genetic prion disease recapitulating cognitive, motor, and neurophysiological abnormalities of the human disorder," explained Dr Chiesa. "This new model allows in-depth analysis of the disease mechanisms and may be useful for testing potential therapies for inherited prion diseases."
The study was financed in part by the NeuroPrion network ('Prevention, control and management of prion diseases') under the EU's Fifth and Sixth Framework Programmes (FP5 and FP6). NeuroPrion is a five-year project ending in December this year that received EUR 14.4 million in funding to coordinate research efforts on prion diseases in order to ensure protection of human and animal health and to avoid harmful economic consequences.
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