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New ALS Protein Could Be a Keystone Molecule is identical in patients with the most common ALS and the inherited form Even though, in humans, the familial and sporadic forms of the disease are virtually identical symptom-wise, researchers had concerns that at the most basic level, the animal model differed enough between the two to slow progress on therapy for all ALS. But now, a new study by a team of Packard Center investigators and their colleagues at several U.S. research institutions, used forefront techniques to show that both familial and sporadic ALS produce an identical complex of flawed protein - one never seen before - in the spinal cord. The protein appears unique to ALS, and tissue samples from healthy people or from other neurodegenerative diseases - Huntington's, Parkinson's and Alzheimer's - don’t show it. “We had assumed that at some point, fALS and sALS had to have some downhill pathway in common in the nervous system,” says Packard director and researcher Jeffrey Rothstein, “but evidence for that has been elusive until now. “Finding what looks like a common underlying pathology, though, makes our studies with the animal models relevant for both forms of ALS,” Rothstein adds, “and it means we can still push ahead with the therapies we’re planning to test.” The study appeared in the July issue of the Proceedings of the National Academy of Sciences. Both old and new studies center on the molecule, superoxide dismutase or SOD1, an enzyme in plentiful supply in the body. A mutation in the gene coding for SOD1, found in patients with a family-based form of ALS, causes their disease. Some 110 different mutations of SOD1 exist - Packard scientists and others have shown - each making a slightly different, misfolded protein capable of bringing on the disease, though no one knows exactly how. No mutations have appeared, however, in the SOD1 that the 90 percent of patients with sporadic ALS produce. But because existing techniques for revealing misfolded proteins aren’t particularly sensitive, scientists have never been totally sure that oddly-shaped SOD1 isn’t found in tiny quantities in patients with the more common disease. Now, in the present study, researchers employed a new, ultra-sensitive way to try to rule that out. The technique takes advantage of the fact that different folded proteins respond differently to a specific binding agent. Such tagging makes the molecule more obvious. The result, from spinal cord tissue samples from autopsied patients, was that an altered form of SOD1 was present in patients with sporadic ALS. Also telling is that the same form was found in the smaller percentage of familial ALS patients who don’t have the SOD1 mutation. “Does this altered SOD1 somehow help cause sporadic ALS? Could it in some way accelerate disease?” Rothstein asks. “This study doesn’t answer that. Only future experiments will tell. But these findings are intriguing,” he says, “and certainly bear investigating.” Don W. Cleveland, of the Ludwig Institute for Cancer Research at the University of California, San Diego, and Jeffrey D. Rothstein, with the Johns Hopkins Medical Institutions were the Packard members of the team. Other authors were with the California Pacific Medical Center Research Institute, San Francisco and the University of Pittsburgh School of Medicine. |
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