Memory and behavioural problems reversed in mice infected with prions that cause a disease similar to human vCJD
Problems with memory and social behaviours can be reversed in mice infected with prions that cause an illness similar to vCJD in humans.
Diseases, such as vCJD in humans, BSE in cattle or Scrapie in sheep, are caused by a build up of abnormally shaped versions of proteins called prions in the brain.
Scientists led by Dr Giovanna Mallucci at the Medical Research Council's Prion Unit have shown that stopping production of naturally occurring prions in the mice reverses the effects of the disease on brain function. The study is published in the journal Neuron. The scientists say the work demonstrates that targeting natural prions could bring hope for early intervention in people with prion diseases. But they warn that any therapies will rely on being able to diagnose prion diseases before the brain is permanently damaged.
In prion disease, ‘rogue’ prions are formed from naturally occurring normal prion protein, which changes its shape and starts to accumulate. This abnormal form is associated with the disease state and with infectivity. Prions replicate by converting more natural prion protein into the abnormal form.
Dr Mallucci's research team used genetically engineered mice to study the effect that stopping prions from replicating has on symptoms and progression of prion disease. Dr Mallucci said: “This work evolved from earlier studies we had performed. We had originally reasoned that removing the normal prion protein in diseased animals would prevent further formation of the rogue prions and prevent disease progression.”
She explained:
“We first generated mice which we had engineered such that the production of the normal prion protein is switched off at around 9 weeks of age by production of an enzyme, called Cre recombinase, which removes the gene that makes the normal protein in brain cells. We then compared those mice with others in which the normal protein was not removed.”
“Our earlier work established that removing the normal prion protein reversed characteristic early ‘spongy’ changes in the brains of prion infected mice. What we did now was to concentrate on investigating the clinical significance of this early prion-related damage, and the effects on brain function when the changes were reversed when natural prions are depleted.’’
The team found that in the early stages of disease, in parallel with the development of ‘spongy’ change, all of the mice started to have problems with memory and behavioural tests. But mice in which the normal prion protein was removed experienced a reversal in symptoms and recovered normal natural behaviours and the ability to learn and remember. In comparison, in mice in which the gene was not switched off no reversal of symptoms was observed, and these mice progressed to develop severe symptoms and died.
So the team have shown that brain cells recover their function as well as recovering from early degenerative changes if prion conversion is prevented early enough in disease.
Dr Mallucci is cautiously hopeful that this discovery could eventually benefit people who show the first symptoms of prion diseases before they have lost significant numbers of brain cells. This hinges on the availability of an early diagnostic test that can pick up the illness in its earliest stages. She concluded: ''We still need to know more about the role that natural prions play in the body but this research in mice suggests that naturally occurring prion protein is a valid target for therapy that aims to reverse the early symptoms of prion disease and stop these diseases from progressing further. Our results have shown that early problems with brain function can be rescued in mice. Put simply, if there is no natural prion protein present in the brain the conversion process to the ‘rogue form’ cannot take place and damage to brain cells will be prevented. The challenge now is to be able to detect early disease in humans and to develop treatments that can remove normal prion protein. The MRC Prion Unit has a strategy to identify drugs that can bind to the native form of prion protein as a first step in this process.''
Notes to editors
Two JPEG images of mice are available:
Image 1: Healthy mice and rats actively 'burrow' food pellets from a tube and carry them out into their cage. Mice with early prion infection lose the motivation to do this. When natural prions are removed, the burrowing behaviour recovers.
Image 2: Healthy mice explore new objects and remember those they have seen before. Prion infected animals lose the ability to remember familiar objects but regain it when the natural prions are removed.
For further information, or to arrange an interview with Dr Giovanna Mallucci please contact the Medical Research Council press office on 020 7637 6011 or press.office@headoffice.mrc.ac.uk. Out of hours please phone 07818 428 297.
Targeting cellular prion protein reverses early cognitive deficits and neurophysiological dysfunction in prion-infected mice, Mallucci et al is published in the journal Neuron.
The Medical Research Council is dedicated to improving human health through excellent science. It invests on behalf of the UK taxpayer. Its work ranges from molecular level science to public health research, carried out in universities, hospitals and a network of its own units and institutes. The MRC liaises with the Health Departments, the National Health Service and industry to take account of the public’s needs. The results have led to some of the most significant discoveries in medical science and benefited the health and wealth of millions of people in the UK and around the world. www.mrc.ac.uk
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