Researchers show that prion disease symptoms & pathology are reversible

Experiments by researchers from the Institute of Neurology in London and the University of Birmingham’s Department of Neurophysiology show that the behavioural symptoms and pathologies associated with prion diseases can be reversed, if the infection is detected early on. The findings suggest that it may be possible to develop a cure for variant Creutzfeldt-Jakob disease (vCJD), a human prion disease.

To date, 158 British people have died from vCJD, and 7 more are known to be infected. And research performed last year by John Collinge, the senior author of the current study, suggests that human prion diseases may have an incubation period of up to 50 years, and that an epidemic of vCJD may lie ahead. It is widely believed that the transmission of prion diseases to humans occurs by the consumption of infected meat, which contains an abnormal version of a protein found in all nerve cells.

The full name of the prion diseases – spongiform encephalopathies – means “sponge-like brain diseases”, and describes the appearance of infected nervous tissue, which becomes dotted with small “holes” as the disease progresses. These holes make the tissue resemble a sponge, and eventually interfere with the ability of nerve cells to conduct electrical impulses. This is followed by damage to synapses and death of affected nerve cells. But the symptoms of prion diseases, which include loss of motivation, cognitive impairment, and unsteady gait, are exhibited before a diagnosis can be made, and before any cell death occurs.

The new work, which was led by Giovanna Mallucci and has just been published in the journal Neuron, involved the creation of a strain of transgenic mice. This involved making a genetic construct consisting of a copy of the prion gene containing DNA sequences that are recognized by an enzyme which snips DNA and rearranges it by a process called recombination. The animals were infected with abnormal prion protein at around one week of age. Soon after infection, all the mice displayed the cognitive and behavioural symptoms of prion infection. They exhibited impaired recognition of familiar objects, and burrowing behaviour was reduced due to a lack of motivation. These symptoms were correlated with damage to the dorsal region of the hippocampus; immunohistochemical staining showed reduced levels of a nerve terminal protein called synaptophysin 1, indicating that synapses were damaged, and electrophysiological recordings confirmed that there was also a decline in synaptic function in that region of the brain.

When the mice reached 10 weeks of age, the gene encoding the DNA recombination enzyme was activated in one group of mice, so that the prion gene was disrupted and synthesis of the prion protein ceased. In the other group, the prion gene was kept intact, and the cells continued to synthesize the protein. It was found that, in the mice that had stopped expressing the prion gene, depletion of the protein led to a reversal of the disease symptoms and pathologies. The memory of infected animals, as measured by their performance on the object recognition task, was restored, and they performed as well as uninfected control mice. The improved performance paralleled a reversal of pathological hallmarks of prion diseases: antibody staining showed that synaptophysin 1 levels in the dorsal hippocampus had returned to normal, and electrophysiological recordings showed a recovery of synaptic function. On the other hand, in the group of mice that continued to express the prion gene, the symptoms progressed, leading ultimately to the animals’ death.

This is the first study to show that the symptoms and pathology of prion diseases are reversible, and the findings may have implications for other neurodegenerative diseases, particularly Alzheimer’s. However, the reversal of symptoms and pathology observed in this study was only possible because the depletion of prion protein was induced in the very early stages of infection. The recovery of function may only have occurred because the mice were so young; in older animals, in which there is less brain plasticity, this recovery may not have occurred. Mallucci and her colleagues therefore stress that any possible treatment for vCJD – based on drugs which block prion protein function – could take years to develop, and would depend on a blood test that can detect prion diseases in the early stages, before any irreversible damage to the brain has occurred. Furthermore, because the prion protein is a normal constituent of nerve cells, the long-term effects of preventing its synthesis are unclear.

Reference:

Mallucci, G. R. et al (2007). Targeting Cellular Prion Protein Reverses Early Cognitive Deficits and Neurophysiological Dysfunction in Prion-Infected Mice. Neuron 53: 325-335.

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