The Mouse With Sleeper Toxins

500px-neuron_with_oligodendrocyte_and_myelin_sheath-2svgStudying a disease using an animal model is not as simple as merely replicating it. For instance, a variety of techniques have been used in animals to simulate the neurological disorder multiple sclerosis, where the protective myelin sheath that wraps around neuronal axons is lost, but each method has its advantages and disadvantages. Scientists have used toxins to directly damage myelin, but the effects are unpredictable and hard to control. Triggering an autoimmune response against myelin imitates the true biological mechanism of MS, but the immunological and neurological effects are difficult to separate.

Because Brian Popko, professor of neurology at the University of Chicago Medical Center, is interested in how to remyelinate neurons that lose their myelin sheath, a different model was required. What if you could create a mouse where the myelinating cells, called oligodendrocytes, die off on command, producing a more controlled demyelination independent of immune system effects? Such a model would allow for studies of how the nervous system responds to demyelination, and how it may recover – information that could be valuable for developing and testing new drugs for MS.

In a paper published today by the journal Brain, Popko’s group describes just such a mouse. Years of genetic engineering and selective breeding have produced a new mouse model where researchers can trigger demyelination, and then watch closely as the mice develop the telltale signs of neurological disease: muscle tremors, difficulty walking and staying upright. But incredibly, in a matter of weeks, most of the mice have recovered, exhibiting motor behavior indistinguishable by the naked eye from normal mice. The central nervous system (CNS) mounts a natural comeback – and the next step is to figure out how.

“The one thing that this model shows without question is that the central nervous system has an extremely robust potential to remyelinate,” Popko said. “We’ve pretty much wiped out all CNS myelin, and yet it recovers, the mouse comes back to normal.”

From start to finish, the mouse’s brush with neurological disease is about 2-1/2 months long. Each mouse is bred with a genetic “sleeper agent” – the toxin diptheria, known in humans as a source of upper respiratory illness. Popko’s laboratory devised a way to place a dormant diptheria toxin inside oligodendrocytes, a weapon that only switches on when the mouse is injected as an adult with a common drug. Within three weeks, the oligodendrocytes have been wiped out, and the mouse’s axons are left without their protective myelin. At five weeks, the mouse shows severe neurological symptoms, completely unable to run on a treadmill test called the Rotarod. But five weeks later, the mouse is able to log-roll the Rotarod as well as normal mice, and microscopic pictures find that their axons have a new, albeit thin, coating of myelin.

Videos of the mice before and after recovery can be seen at the Myelin Repair Foundation, a non-profit organization that helps fund Popko’s research.

“If you look at these videos, it explains why the Myelin Repair Foundation exists,” Popko said. “A mouse without myelin is very sick, while the mouse who has gone through myelin repair is doing quite well.”

Publishing the new model is just the first step along a hopefully fruitful research path. Now that the arc of myelin loss and recovery has been charted, Popko’s group plans to look at whether the ability to remyelinate decreases with age, as has been suspected in human MS patients. Another intriguing lead is the radically different recoveries of male and female mice after demyelination in the Brain study: while a majority of males recovered completely, nearly all of the females died. That gender inequality may line up with the observation in humans that women are as much as four times more likely to contract MS, but the reason for the sex difference remains mysterious.

But the primary goal is to use the mouse model as a testing ground for drugs designed to help remyelination along in patients with MS or other myelination disorders. One such therapy, an antibody against a receptor called lingo developed by the pharmaceutical company Biogen-Idec, has shown promise in animal studies but has yet to be tested in clinical trials. Other myelination therapies may lie in the future, perhaps based on one of the other animal models created in Popko’s laboratory looking for genes and proteins involved in myelination. If any of these strategies turn out to be a valuable new tool for fighting MS, the mice with sleeper toxins in their cells will be deserving of thanks.

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Traka, M., Arasi, K., Avila, R., Podojil, J., Christakos, A., Miller, S., Soliven, B., & Popko, B. (2010). A genetic mouse model of adult-onset, pervasive central nervous system demyelination with robust remyelination Brain DOI: 10.1093/brain/awq247

About Rob Mitchum (526 Articles)

Rob Mitchum is communications manager at the Computation Institute, a joint initiative between The University of Chicago and Argonne National Laboratory.

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