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CENTER STUDY EXPLAINS A MAJOR SIGN OF DISEASE IN ALS CELLS The fact that it's reversible sparks optimism, scientist says. New studies by Packard Center scientist Jeffrey Elliott and his research team strongly suggest answers to two of the major mysteries of amyotrophic lateral sclerosis (ALS), namely, why the disease mostly affects adults and why it primarily targets cells in the spinal cord. The work--in classic ALS animal models--is also newsworthy because it shows it's possible to reverse a key process that goes awry in diseased spinal cords. "In animal models of Huntington's disease, a similar reversal of abnormal pathways in mouse models turned their disease around," says Elliott. "We're hoping that will also occur in ALS models. Then we'd have a truly sensible target for therapy." Elliott's work centers on the appearance of masses or clumps of a protein called SOD-1 in the spinal cords of patients with the familial (heritable) form of ALS. The clumps or aggregates also appear in spinal cords of ALS mouse models that carry the same mutant gene as people with familial ALS. Aggregates appear in the model mice before disease symptoms set in. While nobody has shown that aggregates cause the death of cells, the association of the two is believed significant by many scientists. In the study, the researchers studied cells in lab-cultured spinal cord sections taken from model ALS mice. They showed that aggregates can result from upsets in a cell's natural housekeeping process---the removal of proteins by cell structures called proteasomes. Normally, cells' mutant, misfolded or unwanted proteins get digested by proteasomes. But when Elliott artificially damped down proteasome activity, aggregates of SOD1 protein quickly appeared. A 30 percent drop could cause clumps of protein to appear in 48 hours. "We think even smaller changes in proteasome activity might be enough to trigger aggregate formation but more slowly, over months or years," says Elliott. "That could well be part of the process that occurs in human disease, particularly the more common form of ALS." When the team examined a variety of tissues for proteasome activity, they found the least in cells of the central nervous system. Liver, for example, has far greater proteasome activity. "This might account for the vulnerability of spinal cord cells in ALS." And the fact that proteasome function drops as cells age might have something to do with disease appearing in adults, the scientists say. Most interesting, when Elliott's team removed inhibitors to proteasomes and restored a normal level of their function, the aggregates began to disappear. The "vanishing trick" took much longer than the aggregates' formation but, says Elliott, "it did occur." Now Elliott's searching for internal or external triggers for altered proteasome activity in people, as well as for the mouse models. Elliott and his team have their laboratories at the University of Texas,
Southwestern Medical Center in Dallas. |
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