Sponging Up Glutamate?
Good Idea

Margaret Sutherland explains transporters’ benefits.

A new study by Center scientist Margaret Sutherland, Ph.D., not only shores up a long-held idea on a major source of cell damage in ALS but also shows something can be done to fix it, at least in mice.

Sutherland’s study touches broadly on the idea of excitotoxicity—that too much of the nerve transmitter glutamate is toxic to motor neurons. Then it focuses on the likelihood that glutamate pools because normal cell methods of sopping it up aren’t working properly.

Both ideas stemmed, in part, from evidence a few years ago from Center Director Jeffrey Rothstein, M.D., Ph.D., that the brains and spinal cords of most ALS patients come up short in the molecule that ferries excess glutamate out of harm’s way. That molecule, called EAAT2, is a cell membrane protein that whisks glutamate from relatively fragile motor neurons and into bodies of nearby astrocyte cells, where it gets recycled.

Sutherland reasoned that adding healthy EAAT2 to astrocytes might slow the course of ALS or somehow lessen its damage. The more transporter, the thinking went, the more glutamate cleaned up. Using current cell-engineering methods, Sutherland’s team inserted a gene for the molecular equivalent of an EAAT2 on-switch—one that would work in astrocytes—in early- stage mouse embryos. The resulting mice produced more than the usual amount of EAAT2.

Next, she bred the transporter-overproducing mice with those that develop the rodent equivalent of ALS. These model mice carry a mutation—the same as in humans with hereditary forms of ALS—that lowers their number of active EAAT2 transporters.

Because of the way genes are randomly distributed in offspring, the cross produced a variety of mice. But those carrying both the mutation and the ability to over-express EAAT2 were protected, to a degree. The double-gene mice lived, on average, 175 days, as opposed to the ALS models’ 140 days. Follow-up studies showed that the hoped-for glutamate transport was indeed taking place at the cell level and that the toxic chemical wasn’t accumulating.

“As pleased as we were to see this,” says Sutherland, “we know the gene approach isn’t practical as therapy.” Sutherland, who’s also a researcher at George Washington University, is working with a company to develop drugs that can mimic the effect of the EAAT2 switch and increase transporter presence.

Barring that, she says, an agent that could maximize what EAAT2 there is, making sure it’s always available in the cell membrane, would likely help as well. Sutherland’s also eager for upcoming tests of stem cells coaxed by researchers to produce high amounts of transporter. “We hope they, too, will have a protective effect on motor neurons when injected into animal ALS models.

“I suspect anything that could increase glutamate transport,” says Sutherland, “would be an exceptional help.”

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