It's been known since the early 1990s that mutations in the superoxide dismutase-1 (SOD1) gene can result in the production of any number of varieties of improperly folded (misfolded) SOD1 protein, and that these misfolded proteins can cause familial amyotrophic lateral sclerosis (ALS). Now, researchers have found that normal (nonmutated) human SOD1 protein also is prone to misfolding and can cause the disease, at least in mice.
Note: FamilialALS, where there is more than one occurrence of the disease in a family, accounts for 5 to 10 percent of all ALS. By contrast, 90 to 95 percent of ALS is labeled as sporadic because no evidence exists of the disease occurring in any of the affected individual's relatives.
The new data add to a growing body of evidence that suggests that normal human SOD1 protein:
The findings also lend support to the hypothesis that in ALS — and in several other neurodegenerative conditions, such as Alzheimer's disease and Parkinson's disease — proteins that cause the disease when they're mutated also may cause problems when they're not mutated.
In order to determine whether normal human SOD1 protein can cause ALS, the researchers created mice that produce the protein at levels approximately 25 times higher than normal levels of mouse SOD1. These are similar to the high levels of mutant human SOD1 in the commonly studied G93A mouse model of ALS, and are necessary to cause disease within the mouse's short life span.
The mice exhibited several features indicative of an ALS-like disease, including:
The research team, based at Umeå University in Sweden, published its findings online Oct. 1, 2012, in Human Molecular Genetics. The full report is available for purchase: Expression of Wild-Type Human Superoxide Dismutase-1 in Mice Causes Amyotrophic Lateral Sclerosis.
The researchers caution that levels of normal human SOD1 protein in the experimental mice were far higher than normal levels of mouse SOD1 would be, or human SOD1 would be in humans. Higher levels of SOD1 would mean higher levels of misfolded SOD1. However, the researchers note, there is evidence that even very small amounts of misfolded SOD1 can cause disease.
Claudio Hetz at the University of Chile in Santiago has an MDA grant to study protein misfolding and mislocation in ALS. With colleagues, Hetz has identified three foldases (enzymes that promote correct protein folding) that can cause normal SOD1 protein to misfold.
In a 2010 study, researchers determined that misfolded SOD1 protein, unaccompanied by an SOD1 mutation, appears to underlie at least some sporadic ALS.
Familial and sporadic ALS were linked via SOD1 protein and nervous system support cells called astrocytes in a 2011 study.
Isis Pharmaceuticals of Carlsbad, Calif., in March 2010 launched a phase 1 clinical trial trial (NCT01041222 at ClinicalTrials.gov) of the experimental antisense therapy ISIS-SOD1-Rx, a compound designed to block production of SOD1 protein. Results showed the drug to be safe at low doses. Although the treatment is designed for people who have ALS caused by a mutation in the SOD1 gene, its ability to reduce SOD1 protein levels potentially could be of benefit in sporadic ALS associated with misfolded SOD1 as well.
About Clinical Trials
A clinical trial is a test, in humans, of an experimental treatment. Although it's possible that benefit may be derived from participating in a clinical trial, it's also possible that no benefit, or even harm, may occur.
MDA has no ability to influence who is chosen to participate in a clinical trial.
To learn more, see Learn About Clinical Studies and Being a Co-Adventurer, which is about neuromuscular disease clinical trials. To see a continuously updated database of clinical trials, go to ClinicalTrials.gov.