Deficits in protein-metal complexes may underlie SOD1-ALS: Study
New tool finds protein lacking metal ions in nervous system of mouse model
Changes in how the SOD1 protein associates with metal molecules seem to be key for how mutations affecting this protein drive amyotrophic lateral sclerosis (ALS), according to a study using a novel imaging technique.
Findings represent “a very early step towards” new ALS treatments, while also showing “an exciting new route for understanding the molecular basis of other diseases in unprecedented detail,” Helen Cooper, PhD, the study’s lead author at the University of Birmingham, England, said in a university news release.
The study, “Mass spectrometry imaging of SOD1 protein-metal complexes in SOD1G93A transgenic mice implicates demetalation with pathology,” was published in Nature Communications.
SOD1 normally found in dimer complex, two bound proteins with metal ions
Although the causes of ALS aren’t fully understood, genetic mutations are known to underlie a minority of cases. Mutations in the gene that provides instructions to make the SOD1 protein are among the disease’s most common, accounting for up to 1 in 5 cases of familial ALS and 1 in 50 cases of sporadic disease.
The SOD1 protein is a metalloenzyme, meaning that it’s normally found in a dimer complex (two SOD1 proteins bound together) with certain metal ions, specifically copper and zinc, in the middle. But SOD1 gene mutations can destabilize the protein and prevent it from forming dimers, resulting in an unstable protein that is prone to forming toxic clumps.
It hasn’t been clear, however, whether ALS-causing mutations also affect the ability of SOD1 protein to bind the metal ions, largely due to the limits of current technologies.
Using tissue samples from a well-characterized mouse model of SOD1-associated ALS, scientists at the University of Birmingham and the University of Sheffield, also in England, investigated the metal state of SOD1 proteins using a newly developed technique called native ambient mass spectrometry imaging.
New technique found protein in dimers and unbound in nice brains, spinal cords
This technique “is a label-free molecular imaging technique with the unique capability to identify and map the distribution of endogenous [naturally occurring] protein complexes within tissue sections, including metal-bound proteins,” the researchers wrote.
Results showed that, in certain parts of mice brains and spinal cords, the SOD1 protein was found in dimers and as a single protein lacking their normal metal complex. The specific regions of the nervous system where SOD1 lacked metal are among those hardest hit in ALS, implying that the lack of metal plays a role in driving disease processes. Notably, other molecular modifications of the SOD1 protein didn’t show an association with disease-related regions.
“This approach is the first to show that this form of SOD1 correlates with the pathology” of ALS, Cooper said.
The lack of metal ions likely is linked to SOD1 taking on an abnormal conformation (molecular shape) that drives disease, the researchers said. But it’s not clear whether this lack of metal causes the protein to misfold, or if the protein misfolds first and is then unable to form normal metal complexes, they noted.
Whatever the case may be, the scientists said these findings “have implications for understanding the role of SOD1 toxic gain of function in ALS, which is particularly relevant in the context of therapeutics which reduce mutant SOD1 levels.” Qalsody (tofersen), for instance, is a SOD1-targeting medication conditionally approved to treat SOD1-associated ALS in the U.S. and the European Union.
More broadly, these findings provide a proof-of-concept for using the novel imaging technique to investigate the molecular details of protein dysfunction in diseases like ALS, the researchers said.
“We look forward to using the technology further to explore why motor neurons die and find new interventions for those affected by [ALS],” said Richard Mead, PhD, a study author with the Sheffield Institute for Translational Neuroscience.
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