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In ALS, It’s Not the Number of Ailing Astrocytes That Counts The spinal cord after an auto accident or some other physical trauma could best be described as being in a biological uproar. A wide variety of cells disappear. The chemical environment changes. And of interest to Packard researchers is the sharp upturn in the number of astrocytes. The star-shaped cells that are motor neurons’ companions quickly become far more common - often within 24 hours of injury. This jump is likely protective, studies show; if you block the astrocyte response in lab rats after a trauma, for example, injury is much greater. “But in ALS, important differences exist,” says Packard scientist Nicholas Maragakis. Certainly, as in trauma, astrocytes increase in both animal models of the disease and in the humans who have it. The numbers in both are comparable. But somehow, any neuroprotection that astrocytes offer after a cut or a blow isn’t apparent in ALS. “We really understand very little about how these cells behave before or after symptoms appear, Maragakis explains, “and what’s behind it.” So he and colleagues aim to change that. A decade of research, much of it in Packard labs, shows that more than numbers of astrocytes increase in injury or disease. The cells themselves balloon out and their internal chemistry changes as different genes switch on or off. And a host of recent studies in animal models of ALS points to a role for ailing astrocytes in motor neuron death. Astrocytic molecules that clear toxins from the motor neuron environment, for example, are in short supply. And clumps of abnormal protein clutter astrocytes’ cytoplasm. “By the time ALS symptoms appear,” Maragakis explains, “astrocytes are clearly far from normal and become more so as the disease continues.” They may not start ALS, but the diseased cells certainly have a hand in its progress. The approach Maragakis and other Packard scientists are taking is thorough: to try to block the major astocytic changes in good animal models and see if that either halts or slows ALS. In the first of these studies, just reported in the journal Experimental Neurology, he blocked mature astrocytes from dividing. His team used two animal models of ALS, one, the classic SOD1 mouse model that contains a flawed gene for familial ALS. The other: mice whose central nervous system has been attacked by Sindbis virus. Both types typically have a significantly higher astrocyte count than healthy animals. The result was useful, though not glamorous. The already high astrocyte number didn’t increase. “That suggests that most of them come from a different source - stem cells,” says Maragakis. (New research from his lab has confirmed this alternate stem cell source. Now it appears to be the key one.) And of more interest, survival of the lab animals’ motor neurons or survival of the animals themselves didn’t change. “What this tells us,” he explains, “is that whatever astrocytes do to advance ALS most likely has to do with which genes are active or in how they affect the spinal cord environment. It’s not the actual number of dividing astrocytes that’s so important.” |
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