New study shows potential links between sporadic and familial ALS
Piera Pasinelli, Packard Center's science director.
Researchers first associated mutations in the SOD1 gene with familial ALS in 1993, one of the first times that a specific gene had been associated with the illness. Further studies showed that the SOD1 protein doesn’t work properly even in sporadic ALS patients without a known mutation in the gene, although scientists weren’t sure exactly what was causing this protein to malfunction. A new study published today in the Proceedings of the National Academy of Sciences by Packard Center Science Director Piera Pasinelli showed that SOD1 is over-oxidized and doesn’t fold properly in lymphoblasts of sporadic ALS patients with bulbar onset. This over-oxidized SOD1 acquires toxic properties similar to those seen in mutant SOD1, linking mechanisms of toxicity between a subset of sporadic and familial patients respectively.
Previous studies have hinted that wild-type SOD1 may be over-oxidized and unable to perform its normal functions in some ALS patients. Using lymphoblasts derived from ALS patients, Pasinelli and colleagues showed for the first time that this hypothesis was correct. When cells with this over-oxidized wild-type SOD1 were faced with additional oxidative stress from hydrogen peroxide, they were unable to respond to by further increasing oxidation of SOD1. Instead, oxidative stress induced a conformational transformation of the over-oxidized SOD1 making it mis-behave like the mutant SOD1 seen in familial ALS cases, damaging the patients' mitochondria (the powerhouse of the cell). There is a sort of double hit mechanism, Pasinelli and colleagues found, in which an over-oxidized SOD1 and/or mutant SOD1 lower the threshold to an additional insult that, in patients, can be triggered by the environment or by aging.
"So far, this is the first time that it is shown that wild-type SOD1 is modified by oxidation in ALS using patients' cells. This shows a specific mechanism of toxicity of an aberrant wild-type SOD1 in sALS- a mechanism that has been teased out for mutant SOD1 and allows for the design of target-based therapies that have the potential to go beyond the limited numbers of familial SOD1 patients," Pasinelli said. "We used peripheral blood cells, in which the presence of an over-oxidized SOD1 has the potential to become a biomarker to classify different populations of sALS patients."
Much of the research to understand ALS and develop therapies for the disease uses animal models based on SOD1 mutations. A better understanding of the molecular mechanisms shared by sporadic and familial ALS may enable researchers to generalize mutant SOD1 models to ALS disease that doesn’t involve SOD1 mutations. It also may open the door to subtyping ALS patients based on specific biomarkers.
Read the entire study on www.pnas.org
|Researchers have found that wild-type SOD1 in sALS patients with bulbar onset shares toxic properties with mutant SOD1|
|These results may one day allow scientists to develop biomarkers to subtype ALS patients.|