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THREE JOINT GRANTS SUPPORT MORE GRITTY BASIC ALS RESEARCH Last year, several Packard Center scientists teamed up in an official way with the ALS Association (ALSA), doing work supported both by the Center and by timely grants from ALSA. This program’s similar to our joining with the Muscular Dystrophy Association to fund research programs. And both draw scientists and institutions together more powerfully in their common search for a cure. Roughly half of the Center’s research is basic bench science --- the sort that typically provides a boost to the next step, the translational work that will find a therapy. But these joint ALSA/Packard Center studies lie in-between the two. While they’ll provide answers to basic questions, say, about how replacement spinal neurons grow, they have an ALS slant that puts us closer to actual treatment. The most recent joint grants go to support this work: Researcher Doug Kerr has both lab culture and live animal studies to test the ability of stem cells to restore function to damaged spinal cords. With his grant, he’s shown that mouse embryonic stem cells (ES cells) can grow into motor neurons in cell cultures with target muscle cells close at hand. He’s also shown that ES cells can survive in live spinal cords and that, with special treatment, they can send their processes across the cord --- as occurs in nature --- and even a bit beyond. In other words, he’s started stem cells on the sort of path the animal’s original motor neurons travel en route to muscles. (We wrote about this in the Spring ALS Alert: Study Shows New Motor Neurons Cross the Cord) Now Kerr’s testing ways to enhance the ability of ES-derived motor neurons to extend even farther, to reach target muscles in animals. He’ll try a variety of natural agents known to support nerve cells and encourage their growth. “We’ll never restore the original complexity of the motor system,” he says. “But to regain useful function, we may not need to put everything back. A few connections could make a real difference.” ·Why do motor neurons die in ALS? A handful of theories exist, most of them pointing to problems that originate in motor neurons themselves. But a newer idea involves companion cells to motor neurons, the astrocytes, in the downhill slide. Astrocytes maintain motor neurons’ environment. Altering these cells, somehow, could have grave effects, not only on the astrocytes themselves but on motor neurons. Several studies suggest you don’t have motor neuron death unless something goes awry with astrocytes, but those studies could be stronger. Scientists Nicholas Maragakis and Mahendra Rao are using their grant money to isolate both astrocyte and motor neuron stem cells from the SOD1 mice that mimic human ALS. They’re working with stem cells because those cells survive well in culture. Also, stem cells help avoid the too-frequent problem of having cultures tainted with stray cells of other types, as would surely happen if they tried to isolate adult neurons and astrocytes to study. With pure isolated cultures of both types of cells, Rao and Maragakis can mix them to observe healthy motor neurons and astrocytes growing together. Then they can contrast that behavior with the very young motor neurons and astrocytes that come from flawed model mice. By varying which cell type is “sick,” they can see what’s necessary to mimic ALS. And if cells begin to sicken, they can follow what chemical changes occur in the cells along the way. Knowing for sure that motor cells’ problems begin in the astrocyte would set the search for an ALS cure on a whole new track. ·New grantee Elizabeth Fisher has been studying a mouse with a mild but progressive form of motor neuron disease that may shed light on ALS in an unexpected way. The mouse, called “legs at odd angles” or Loa for its odd appearance, has a flaw in a gene that produces dynein, a protein complex that helps drive motor neurons’ retrograde transport. That’s a system to carry key nerve-sustaining molecules from the outermost reaches of the neuron to its cell body. Dynein also carries out other essential housekeeping in nerve cells. Recently, Fisher and her colleagues showed that the mutation in Loa mice lets them carry out much of their cell housekeeping except for the retrograde transport. Then they develop motor neuron disease that looks, internally, very much like ALS. Fisher has begun using her grant for an intriguing experiment in which she crossed traditional SOD1 mice that model ALS with the Loa mice. Naturally, she expected neuromuscular disaster. To her surprise, the offspring have strikingly delayed onset of disease symptoms and once they start, the mice still live more than a third longer than typical SOD1 mice. “There’s some kind of unexpected interaction between the two mutations,” she says, and she wants to explore what it is on the cell level. “We believe there’s a good chance these surprising mice may
shed light on what goes wrong in SOD1 related ALS,” she says, “and
tell us how to treat it.” |
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