A joint research team comprised of scientists from The Scripps Research Institute and Lawrence Berkeley National Laboratory – both in California – have suggested a cause of amyotrophic lateral sclerosis: increased protein instability. The researchers publish their findings in the Proceedings of the National Academy of Sciences.
Amyotrophic lateral sclerosis is also known as ALS, or Lou Gehrig’s disease – after the first well-known personality (a baseball player) to be publicly affected by the disease, back in the 1940s. More recently, the high media profile of the ALS Association’s Ice Bucket Challenge has once again put ALS back in the headlines.
In August, Medical News Today also reported on a study from Scripps Research Institute scientists that examined the role a mutation on the gene C90RF72 plays in ALS.
When someone has ALS, the neurons that control muscles in their body are destroyed. The gradual loss of these neurons – including those that control breathing – almost always leads to death in the years following the onset of symptoms, according to recent data from the Centers for Disease Control and Prevention (CDC).
About a quarter of cases of ALS that are hereditary – and 7% of “sporadic” ALS cases – are known to be linked with mutations on genes that code for a protein called superoxide dismutase (SOD). However, there are nearly 200 variants of mutations on SOD1 genes that are linked with variants of ALS, and experts cannot agree on how these different mutations all lead to the same disease.
One defining feature of SOD1-linked ALS is that clusters of SOD protein appear in the affected motor neurons and support cells. Even in cases not linked to SOD1 mutations, aggregates of SOD and other proteins can be found in affected cells.
Some of the Scripps scientists had previously looked at what they named “framework destabilization” in ALS. According to this theory, mutant SOD1 genes that are linked with ALS all code for structurally unstable versions of SOD protein.
The unstable SOD proteins are unable to fold properly and begin to aggregate with one another. In the framework destabilization hypothesis, this quickly accumulating SOD aggregation – which forms too fast for neuronal clean-up systems to control the situation – somehow triggers ALS.
In the new study, the team looked at how different SOD1 gene mutations variously affect SOD protein stability.
The team found that the most studied mutation, SOD G93A, aggregated more quickly than non-mutated SOD but more slowly than another mutant – SOD A4V – associated with a rapidly progressing form of ALS.
Upon closer inspection, the researchers also observed a difference in the shape of SOD aggregates. The SOD mutations produced long, rod-shaped aggregates, while non-mutated SOD aggregates were found to be more compact and folded in structure.
Examinations of diminished stability in the mutant SOD proteins looked in particular at a copper ion that helps stabilize the protein. The scientists found that, although mutant SODs were able to take up copper ions normally, if they were exposed to mildly stressing conditions, they had a reduced ability to retain the copper.
Both the impaired ability to retain copper and the longer aggregates corresponded with mutations associated with the more severe forms of ALS.
Also, the researchers suspect that mutant SOD causes inflammation and disrupts protein trafficking and disposal systems. The team believes that these disruptions stress and kill the affected neurons.
“Because mutant SODs get bent out of shape more easily,” says Prof. Elizabeth Getzoff, one of the study’s senior authors, “they don’t hold and release their protein partners properly. By defining these defective partnerships, we can provide new targets for the development of drugs to treat ALS.”
Next, the team will confirm the correlation between structural stability and ALS severity in other SOD mutations.
“If our hypothesis is correct,” says David S. Shin, a research scientist who worked on the study, “future therapies to treat SOD-linked ALS need not be tailored to each individual mutation – they should be applicable to all of them.”