Misfolded SOD1 Found in Sporadic ALS Samples

A new study suggests misfolding of the SOD1 protein may be a common contributor not only to familial (inherited) amyotrophic lateral sclerosis (ALS) caused by mutations in the SOD1 gene but to the more common sporadic (noninherited) form of the disease as well.

If confirmed, the findings could mean that many familial and sporadic forms of ALS share a common factor — protein misfolding. The findings also could mean that therapies being developed to combat mutated SOD1 protein could have application beyond familial SOD1-related ALS.

About the new findings

Robert Brown and Daryl Bosco, neurobiologists and ALS investigators at the University of Massachusetts Medical School in Worcester, coordinated the research team, which published its findings online Oct. 17, 2010, in Nature Neuroscience. (MDA did not fund this study. Brown, a neurologist and neuroscientist, is a former MDA research grantee and former director of the MDA/ALS Center at Massachusetts General Hospital in Boston.)

The team found that SOD1 protein molecules made from a normal (nonmutated) SOD1 gene can assume an abnormal and toxic shape after undergoing a chemical change called oxidation. Once oxidized, they can behave much like SOD1 protein molecules made from mutated SOD1 genes, a known cause of familial ALS.

Misfolded SOD1 protein molecules were detected in the spinal cords of four out of nine people who had died of sporadic ALS, and were not seen in 17 people who had died of causes not related to ALS.

"We're now working to determine the nature of the SOD1 modification in patients," Bosco said. "It may be oxidation and/or other perturbations to the SOD1 protein."

The scientists performed experiments showing that misfolded SOD1 resulting from either mutated SOD1 genes or SOD1 proteins oxidized in the laboratory can impair the transport of substances along nerve fibers, a problem believed to contribute to the ALS disease process.

The idea that SOD1 can misfold in the absence of an SOD1 gene mutation has been previously proposed, although the idea has been controversial, with many researchers finding that misfolded SOD1 is not a factor in sporadic ALS.

Detecting misfolded proteins is usually accomplished by employing proteins called antibodies as molecular "magnets." Researchers design antibodies that stick to particular parts of proteins and can thus identify them.

The investigators on the current study say they have a new antibody, C4F6, which recognizes a different part of the SOD1 molecule from that recognized by previously reported SOD1 antibodies. They say the C4F6 antibody is particularly good at reacting with misfolded SOD1 but not with normally folded SOD1; and that, unlike other methods to detect SOD1 variations, their approach doesn't artificially alter the SOD1 molecules it targets.

The findings parallel recent results from other studies showing that the TDP43 protein and possibly the FUS protein can misfold and aggregate (clump together) in ALS cases with and without ALS-causing mutations in genes for TDP43 or FUS. (See SOD1 Versus Other ALS: Apples and Oranges?; What's going on with TDP-43?; and Progranulin deficiency leds to toxic TDP43 behavior.)

However, it isn't known whether misfolding or aggregation of proteins in the absence of genetic mutations is a fundamental cause of ALS or a downstream effect of a true cause of the disease.

The new findings about misfolded SOD1 in sporadic ALS suggest it could at least contribute, if not cause, the disease, since the misfolded SOD1 was found to interfere with transport of substances along nerve fibers.

Meaning for people with ALS

The new findings, if confirmed, point to a common mechanism underlying familial SOD1-related ALS and sporadic ALS, which accounts for 90 percent to 95 percent of all ALS cases.

That's good news for the ALS community, since most laboratory experiments to identify treatments are conducted in rodents with SOD1 mutations, and no one has been certain whether findings in these rodents offer valid predictions of what a treatment will do in humans with the sporadic form of the disease.

In addition, misfolded toxic SOD1 provides a clear target against which therapies can be developed.

 

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