|
|
|
|
|
|
|
With Metals in Mind: Copper
could be a culprit in Lou Gehrig disease June 2, 2003 Ten years ago, researchers linked familial amyotrophic lateral sclerosis (FALS) to mutations in SOD1 (superoxide dismutase 1), which encodes a copper-containing superoxide dismutase enzyme known as CuZnSOD. Because this enzyme needs copper and zinc to function, the association between SOD1 and FALS led researchers to wonder if copper has an etiological role in the onset or progression of this fatal neurodegenerative disease, also called Lou Gehrig disease. The inherited form comprises about 10% of ALS cases; most cases are sporadic, meaning there is no known family history. Ten years later, scientists still hotly contest the evidence. "Most people would agree that there is laboratory evidence to suggest that metals play a role," says Valerie Culotta, Johns Hopkins University, "but these [neurodegenerative] diseases are far more complicated than what can be done in a test tube." Another researcher, Thomas O'Halloran of Northwestern University, says, "Right now, a lot of fingers are being pointed at metals." Copper, like other metals, is an essential trace element, but it has a huge potential for damage. "Too much copper in the wrong place will catalyze a whole slew of oxidative reactions," explains Ashley Bush, a researcher at Harvard University. CuZnSOD is a protective antioxidant, but if mutant SOD1 somehow renders CuZnSOD unable to bind copper correctly, many things could go wrong. One of the proposed FALS etiologies, the oxidative damage hypothesis, says that copper-mediated oxidative damage causes FALS. The other, more popular oligomerization hypothesis says that CuZnSOD misfolding and aggregation causes FALS. The latter may or may not involve copper. In a controversial 2002 study, Philip Wong of Johns Hopkins and his coauthors appeared to have debunked the oxidative damage hypothesis by showing that knockout CCS-/- mice still develop ALS-like disease.1 The authors wrote that CCS encodes a metallochaperone that guides copper through the cytoplasm to its binding site on the CuZnSOD protein. Without it, copper can't reach its destination. Because the knockouts developed disease without copper-bound CuZnSOD, the authors reasoned that copper-dependent activity of mutated CuZnSOD plays no role in FALS pathogenesis. This implies that copper-mediated oxidative damage has nothing to do with FALS: If copper can't bind to CuZnSOD, then presumably, it can't catalyze any oxidative reactions. But, says Bush, CuZnSOD has other, non-CCS-specific sites where copper can bind and cause damage. It was a "nice experiment," he says, but it left "quite a few mysterious findings that haven't been explained." Although the authors did not conclude that copper-mediated oxidative damage does not cause FALS, the results were generally interpreted that way. Wong later said that his critics bear the burden of proof.2 FALS researchers are awaiting what might be some of the most compelling evidence thus far that CuZnSOD aggregation is involved. In a forthcoming paper in Nature Structural Biology, John Hart and colleagues at the University of Texas Health Science Center in San Antonio, and Joan Valentine's team at the University of California, Los Angeles, describe how mutant CuZnSOD crystallizes in amyloid-like filaments that are reminiscent of those seen in Alzheimer disease. These particular mutants don't bind metals strongly and don't appear to require copper to aggregate, Valentine says. So, although the findings corroborate the oligomerization hypothesis, they do not necessarily support a copper hypothesis. But with FALS linked to more than 90 distinct mutations in SOD1, many of which bind copper (and zinc) very strongly, there is more ground to cover.4 Copper is not the only potential culprit; some scientists suspect that zinc plays a role. Others wonder about the FALS cases that have nothing to do with SOD1. Last month, for example, an international group of researchers linked FALS to mutations in an entirely different gene, Dnchc1.3 And for some, including Valentine, "The big challenge is to figure out what causes sporadic ALS. Clearly, the pathology is the same, but where does it begin to be the same?" As to whether copper plays a role, Valentine says, "It is too soon to speculate." Leslie A. Pray (lpray@nasw.org) is a freelance writer in Northampton, Mass. References |
|
|
|
|
 |
|||
|
from The Scientist Inc.
