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Tell-Tale Protein Clumping in ALS is Less Complex Than Expected That could be a good thing for potential therapies, researchers sayMore than a decade ago, when scientists uncovered a mutant gene for one type of heritable ALS and saw that its resulting protein, called superoxide dismutase (SOD1) was also flawed, they beheld their first clue to the cause of the vile disease. More exciting, even, was the possibility — because of similarities in all forms of ALS — that the find would ultimately lead to therapy. Today, while cell and animal models of ALS engineered with the mutant human SOD1 gene have vastly advanced knowledge, the answers on how flawed SOD1 contributes to motor neurons’ downfall lie just out of reach. This March, however, a U.S. research team including Packard Center biochemist/neuroscientist David Borchelt brought the truth of the SOD1-ALS connection closer. In two studies reported in the Journal of Biochemistry, the scientists performed the first in-depth analysis of abnormal, microscopic clumps of mutant SOD1 protein that form in motor neurons. They also clarified cell mechanisms that produce them. Protein aggregates are a hallmark of Parkinson’s and Alzheimer’s and other neurodegenerative diseases. Though the makeup and timing of the deposits varies according to disease, the fact that they're toxic seems certain. In ALS, aggregates appear both in animal models and in humans with the disorder. And earlier animal model work in Borchelt's lab has shown that clumped mutant SOD1 appears with the onset of disease symptoms. Until now, however, no one had closely analyzed the aggregates. Knowing their makeup could provide clues to the process that made them and, ultimately, perhaps, explain why they're toxic. In one study, Borchelt and a scientific team at UCLA, led by Julian Whitelegge and Joan Valentine, extracted aggregated SOD1 from spinal cords of three different varieties of mutant SOD1 mice, all of which were models for ALS. Using a variety of biochemical techniques, including mass spectroscopy and sophisticated chromatography, they showed mutant SOD1 to be the only protein found consistently in the clumps. "This suggests that aggregating comes naturally to abnormal SOD1 molecules," Borchelt says; "by itself, then, mutant SOD1 could be responsible for the masses we see in cells." The clumping might be part of cell attempts to compact the protein so its toxic portions are hidden. "We won't know what the clumps do, though, until we find how to keep them from forming," he adds. To that end, the scientists are investigating what triggers aggregates. Earlier work hinted that oxidative stress — the sort of insult that a number of environmental events can deliver — might have a role in making mutant SOD1 "sticky." But this new research says that's unlikely, that something intrinsic in the molecule is at work. "These studies will help us identify the events crucial to generating substances toxic to cells in ALS," says Borchelt, "while they'll also reveal chemical targets most likely to respond to therapy." Packard scientist Borchelt heads the McKnight Brain Institute at the University of Florida, Gainsville. |
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