Thursday, April 10, 2008


To: The ALS Community Date: April 10, 2008 Subject: Robert Packard Center ALS News
Network Article available online at:

That could be a good thing for potential therapies, researchers sayMore than a decade ago, when scientists uncovered a mutant gene for onetype of heritable ALS and saw that its resulting protein, calledsuperoxide dismutase (SOD1) was also flawed, they beheld their firstclue to the cause of the vile disease. More exciting, even, was the possibility * because of similarities inall forms of ALS * that the find would ultimately lead to therapy.Today, while cell and animal models of ALS engineered with the mutanthuman SOD1 gene have vastly advanced knowledge, the answers on howflawed SOD1 contributes to motor neurons' downfall lie just out ofreach. This March, however, a U.S. research team including Packard Centerbiochemist/neuroscientist David Borchelt brought the truth of theSOD1-ALS connection closer. In two studies reported in the Journal of Biochemistry, the scientistsperformed the first in-depth analysis of abnormal, microscopic clumps ofmutant SOD1 protein that form in motor neurons. They also clarifiedcell mechanisms that produce them. Protein aggregates are a hallmark of Parkinson's and Alzheimer's andother neurodegenerative diseases. Though the makeup and timing of thedeposits varies according to disease, the fact that they're toxic seemscertain. In ALS, aggregates appear both in animal models and in humanswith the disorder. And earlier animal model work in Borchelt's lab hasshown that clumped mutant SOD1 appears with the onset of diseasesymptoms. Until now, however, no one had closely analyzed the aggregates. Knowing their makeup could provide clues to the process that made themand, ultimately, perhaps, explain why they're toxic.In one study, Borchelt and a scientific team at UCLA, led by JulianWhitelegge and Joan Valentine, extracted aggregated SOD1 from spinalcords of three different varieties of mutant SOD1 mice, all of whichwere models for ALS. Using a variety of biochemical techniques, including mass spectroscopyand sophisticated chromatography, they showed mutant SOD1 to be the onlyprotein found consistently in the clumps. "This suggests thataggregating comes naturally to abnormal SOD1 molecules," Borchelt says;"by itself, then, mutant SOD1 could be responsible for the masses we seein cells." The clumping might be part of cell attempts to compact theprotein so its toxic portions are hidden. "We won't know what the clumps do, though, until we find how to keepthem 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 anumber of environmental events can deliver * might have a role inmaking 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 generatingsubstances toxic to cells in ALS," says Borchelt, "while they'll alsoreveal chemical targets most likely to respond to therapy."
Packard scientist Borchelt heads the McKnight Brain Institute at the University of Florida, Gainsville.==========================About The Robert Packard Center for ALS Research at Johns Hopkins

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