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New Study Brings What Goes Wrong in Inherited ALS into Focus Work adds to body of research pointing to astrocytes in ALS. The study, done with lab rats, should help researchers seeking therapy for the inherited disease. But the work is also important in understanding the more typical “sporadic” ALS because of implications for pathways likely held in common for both forms of the disease. The report appears in this month’s Proceedings of the National Academy of Sciences. An added benefit: It also offers a plausible idea why ALS targets only motor neurons, out of all the nerve cells in the nervous system. The research centers on receptors on motor nerve cells — neurons — that respond to the nerve transmitter glutamate. When glutamate receptors are stimulated, the neurons that house them fire, tripping normal message-carrying activity. Should the receptors become overstimulated, however—as happens in stroke, epilepsy and ALS — neurons die. Death by overstimulation appears to hinge on the actual structure of the receptor. And a body of work by Robberecht and colleagues shows that structure isn’t fixed but can vary. Part of the new study shows, for example, that two different varieties of rats, Holtzman and Wistar, differ greatly in receptor structure. “This ability to vary is likely one way the body fine-tunes the nervous system to make it more or less responsive to the environment,” Robberecht says. In ALS, however, the fine-tuning apparently goes awry, he says, and motor neurons then become dangerously sensitive to stimulation, in effect, firing themselves to death. And what fine-tunes the receptors? Robberecht’s group showed that neighboring cells called astrocytes hold those reins, in ways that aren’t yet clear. “Some sort of protein secreted by astrocytes ultimately affects the structure of the glutamate receptors,” Robberecht says. Evidence comes from finding that the culture liquid surrounding astrocytes grown from Holtzman rats can protect Wistar rat motor neurons from toxic overstimulation. Other tests with whole pieces of astrocytes showed the same thing. In trying to clarify the fine-tuning process, the scientists analyzed receptors from both types of rats. A higher proportion of glutamate receptors from Holtzman rats had a key building block, called the GluR2 subunit. Those rats resisted overstimulation. Wistar rats, however, with fewer GluR2s, were more likely to succumb. The GluR2 unit is key because something in its structure lets neurons resist the inward rush of calcium ions into neurons, an event typical in disease. High calcium influx is the immediate “trigger” that overstimulates neurons, leading to death. “More specifically, then, we believe that astrocytes secrete a protein that makes motor neurons express GluR2 to a higher degree,” says Robberecht. So where does ALS come in? The researchers found that in rats with flawed SOD1, there’s a roadblock in the astrocyte-glutamate receptor pathway. In rats with the mutant SOD1 gene — the one that causes some inherited ALS in humans — carrying the resulting mutant protein in their astrocytes abolishes the animals’ ability to avoid overstimulation. “It does that,” he says, “by blocking their ability to add the protective GluR2 subunit to glutamate receptors.” Motor neurons of both Holtzman and Wistar rats died when their astrocytes carried mutant SOD1. The find suggests new approaches to therapy. “Putting healthy astrocytes around motor neurons may reduce their vulnerability,” says Robberecht. “It may be easier to correct the environment in the spinal cord by providing such cells than by replacing motor neurons themselves. “We also found it interesting,” he adds, “that of all the neurons in the body, motor neurons — healthy ones, we’re talking about now — have the fewest GluR2 subunits. This could make them naturally vulnerable to neurodegenerative disease.” In addition to being a Packard grantee, Robberecht is also one of the Center’s scientific advisors. |
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