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ON THE TRAIL OF PROTEINS GONE AWRY People with a rare, inherited form of ALS have mutant forms of the gene that codes for the SOD1 protein in cells. And mouse models, engineered to carry that same mutant gene, lose their motor neurons in ways similar to people with the disease. "We know that mutant SOD1 protein typically forms clumps or aggregates in the spinal cords of mouse models and people with familial ALS," says Elliott. "We also know that protein aggregates are common in other neurodegenerative diseases, such as Huntington's or Parkinson's disease. "But one key thing we haven't known--and what might provide a therapeutic target for ALS at some point--is what causes the mutant protein to clump. That's what our work aims to find out." In one study, the scientists focused on abnormal areas in the SOD1 molecule.
They assumed only certain mutated motifs in the molecule-- the biochemists'
term for distinct areas--can alter SOD1 in a way that causes it to clump.
They also looked at two other "innocent bystander" proteins in cells, called SOD3 and CCS, that have several motifs in common with normal SOD1. By causing the same flaws in the "bystander" proteins that appear in mutant SOD1, the scientists got SOD3 and CCS to aggregate--something that such proteins wouldn't normally do. "Our next step is to see if these new aggregates will cause ALS-like disease in mice," says Elliott. "If they do," he adds, "then we'd know that protein structure flawed in a particular way encourages aggregates and somehow causes cell death. We wouldn't be surprised if that's the case." A second study by the Elliott team sheds more light on two major questions in ALS: why does the disease usually come on later in life and why does it largely single out motor neurons in the spinal cord? This study focuses on proteasomes, the microscopic cell organs whose duty is to digest flawed or unwanted protein. Often called the cell's "garbage cans," proteasomes play an active role in cell health. In the new work, Elliott shows a possible relationship between aggregated or clumped proteins in cells and poorly-working proteasomes. By using a drug that slows proteasome activity in ALS model mice, Elliott's team found they could cause protein aggregates to appear. "The more you block proteasomes from acting, the greater the amount of aggregate in cells," he says. Most important, they also found that the clumps of protein could be made to disappear when normal proteasome activity is restored. "This tells us that you can reverse the clumping of protein, under the right conditions," says Elliott. It's something, he says, that could be useful in designing therapy. Further research showed that proteasome activity in the spinal cord
naturally decreases with age, unfortunately, just as production of mutant
protein in the model mice is increasing. Finally, the team found that different tissues of the body vary widely in proteasome behavior. Activity in the spinal cord, for example, is normally far higher than that in liver, kidney and heart--three tissues not harmed by ALS. "So we think it's highly possible that subtle adjustments in the activity of proteasomes could have profound effects on the way mutant proteins accumulate in spinal cord cells. These shifts might play a role in getting a disease like ALS," says Elliott, "or one day, we hope, in reversing it." Dr. Elliott is with the Department of Neurology, University of Texas
Southwestern Medical Center in Dallas. |
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