Floppy proteins linked to ALS

A loss of protein stability has been linked to muscle-destroying disease amyotrophic lateral sclerosis (ALS) by American researchers. Mutations in a gene coding for protein superoxide dismutase SOD is linked to the more severe forms of the disease, which destroys muscle-controlling neurons, the PNAS study states, providing evidence that these proteins are structurally less stable and more prone to form clusters or aggregates. “Our work supports a common theme whereby loss of protein stability leads to disease,” said John A. Tainer, professor of structural biology at The Scripps Research Institute (TSRI), and senior scientist at Berkeley Lab. “The suggestion here is that strategies for stabilising SOD proteins could be useful in treating or preventing SOD-linked ALS,” said Elizabeth Getzoff, professor at TSRI. SOD-linked ALS has nearly 200 variants, each associated with a distinct SOD1 mutation, although they all have the appearance of SOD aggregates in their affected motor neurons and support cells. Scientists probed how different SOD1 gene mutations in a particular ALS hotspot affected SOD protein stability, examining how the aggregation dynamics of the best-studied mutant form of SOD – SOD G93A - differed from wild-type SOD. SOD G93A aggregated more quickly than wild-type SOD, but more slowly than another mutant – A4V – which is associated with a more aggressive form of ALS. Further experiments revealed G93A and five other G93 mutants formed long, rod-shaped aggregates compared to the compact folded structure of the wild-type. SOD proteins that more quickly formed longer aggregates were those that corresponded to more rapidly progressing forms of ALS. Copper ions are normally incorporated within the SOD structure, stabilising the protein but further work revealed that G93-mutants seemed normal in their ability to take up copper ions but had a reduced ability to retain it under mildly stressing conditions, an ability lower for SOD mutants associated with severe ALS. “There were indications that the mutant SODs are more flexible that wild-type SOD, and we think that explains their relative inability to retain copper ions,” said Ashley J Pratt. In short, G93 mutants appear to have looser, floppier structures that are more likely to drop copper ions and therefore more likely to misfold and aggregate. The scientists suspect that deviant interactions of mutant SOD trigger inflammation and disrupt ordinary protein trafficking and disposal systems “Because mutant SODs get bent out of shape more easily, they don’t hold and release their protein partners properly,” said Getzoff. By defining these defective partnerships, we can provide new targets for the development of drugs to treat ALS.” Aggregation propensities of superoxide dismutase G93 hotspot mutants mirror Amyotrophic Lateral Sclerosis clinical phenotypes