Early Fix: Prion disease remedied in mice

Mad cow disease and other brain disorders stemming from prion proteins have long resisted cure. Now, in a test in mice, a prion disease caught early has been reversed.

Prions—misfolded versions of a natural protein called PrP—trigger normal PrP to misfold in the same way. Over time, prion infection kills so many neurons that the brain becomes riddled with holes.

In the new study, neurologist Giovanna R. Mallucci of the Institute of Neurology in London and her colleagues tested whether shutting off the prions’ supply of PrP could alter the course of disease. They worked with genetically engineered mice that make PrP only for the first 9 weeks of life and normal mice that make PrP indefinitely.

The researchers infected both groups, shortly after birth, with prions that cause scrapie in sheep.

At 8 weeks of age, mice in both groups showed cognitive deficits. For example, mice normally spend more time exploring unfamiliar sets of objects than known ones. But the infected mice spent the same time examining strange or familiar arrangements of blocks, indicating that the animals had forgotten familiar arrangements. The mice also lost some of their natural inclination to gather food pellets.

Over the next several weeks, the normal mice continued to decline. However, the transgenic mice, which stopped making PrP, showed improvements, says Mallucci. By 12 weeks of age, they had regained memory and motivation.

Brain changes paralleled the behavioral changes. At 8 weeks old, the mice had lost function at many brain synapses, the junctions where messages are transmitted between neurons. But transgenic mice recovered synapse function soon after their PrP production stopped, Mallucci and her colleagues report in the Feb. 1 Neuron. While PrP’s natural role is poorly understood (SN: 2/4/06, p. 68: Available to subscribers at Good for Something: Prion protein maintains stem cells), mice lacking it don’t seem to suffer consequences, she adds.

This and previous work indicate that the body can clear prions once the PrP supply is eliminated, says Howard J. Federoff, a physician and neuroscientist at the University of Rochester School of Medicine and Dentistry in New York. “This heralds an opportunity for therapeutic development that many in the past might have thought worthless,” he says.

The new study showed that brain impairments occurred in the mice before the appearance of large accumulations of prions and extensive cell death.

“They are seeing [behavioral] alterations before there is massive damage in the brain,” says neuroscientist Claudio A. Soto of the University of Texas Medical Branch in Galveston. “This is very important because [that’s when] these changes are still reversible.”

Eventually, scientists might develop drugs to neutralize PrP, devise a gene therapy to silence the gene encoding PrP, or interfere with RNA to stop the protein’s production, Mallucci says.

However, identifying patients in early stages of prion diseases might be difficult, says Soto. It’s hard to distinguish the initial damage in prion diseases from deficiencies caused by more-common conditions, such as Alzheimer’s disease, he says.

Mallucci hypothesizes that a still-unknown toxic substance is released when prions convert PrP.

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