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Packard Center for ALS Research at Johns Hopkins

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ALS Alert Newsletter | March

The Missing Link?

Two new studies take a fresh look at the relationship between SOD1 and ALS.


Article highlights:

  • Researchers have found that wild-type SOD1 in sALS patients with bulbar onset shares toxic properties with mutant SOD1
  • Toxic SOD1 protein is only found in motor neurons that die in ALS.
  • Together, these two studies will help researchers better understand what triggers ALS regardless of whether it’s related to mutant SOD1.

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. Since this discovery nearly twenty years ago, scientists have been hard at work trying to figure out exactly how changes in the SOD1 protein can lead to ALS. Two new studies published in the Proceedings of the National Academy of Sciences by Packard scientists in March have revealed some important clues in the relationship between SOD1 and ALS.

Only a small percentage of ALS patients carry an inherited mutation in SOD1, yet some studies revealed that the SOD1 protein doesn’t work properly even in sporadic ALS patients without a known mutation in the gene. Packard Center Science Director Piera Pasinelli showed that SOD1 is over-oxidized in certain disease-fighting white blood cells in sporadic ALS patients with bulbar onset. When further stressed, 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.

jon glass
Jonathan Glass, a neuroscientist at Emory University in Atlanta.

In a separate study, Packard researchers Jonathan Glass, a neuroscientist at Emory University in Atlanta, and Jean Pierre Julien, a neuroscientist at Laval University in Quebec, developed antibodies to recognize misfolded SOD1 in motor neurons in familial ALS patients. Although mutant SOD1 is found in every cell in the body, the antibodies only recognized the misfolded SOD1 in dying motor neurons. This indicates, Glass said, that specific changes are happening to SOD1 in motor neurons during the course of disease.

“We still don’t know the cause of ALS. We know that a mutation in certain genes is associated with ALS, but we don’t know why these mutations kill cells,” Glass said. These studies are helping researchers figure out this association.

Oxidation redux.

Since hereditary SOD1 mutations are rare, even among ALS patients, researchers expanded their search for SOD1’s toxic effects into sporadic ALS patients. Previous studies have hinted that wild-type SOD1 may be misfolded, likely through changes induced by environmental stressors, 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 at least part of this hypothesis was correct. In cells from a subset of sporadic patients, scientists found an over-oxidized version of SOD1. 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 the over-oxidized SOD1 to misbehave like the mutant SOD1 seen in familial ALS cases. This change targeted and damaged a protein important to maintain the normal function of the mitochondria (the powerhouse of the cell). It seems that in the portion of sporadic ALS with over-oxidized SOD1, there is a sort of double hit mechanism, Pasinelli and colleagues found, in which the over-oxidized SOD1 lowers the threshold to an additional insult that, in patients, can be triggered by the environment or by aging and, in turn, damages the cells.

"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 sporadic ALS- 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. We also need to confirm using a larger cohort of patients that indeed, this over-oxidized SOD1 correlates with a particular group of sporadic patients."

Protein predictor.

The work of Glass and colleagues asked a slightly different question. Did mutant SOD1 misfold in all the cells in familial ALS patients, or were these folding problems limited to nervous system cells? “A person who is carrying a mutant SOD1 protein is born with that mutation, and lives a good portion of their life before anything happens. The protein is there their whole life, but, for some reason, at age 50 or 60, it starts killing motor neurons,” Glass said. “We wanted to know what happens to that protein that makes it toxic.”

Glass and colleagues created an antibody that would only recognize the toxic form of mutant SOD1 and screened a variety of human and mouse tissues to see in which types of cells this protein could be found. Using tissues from autopsies of familial ALS patients with an SOD1 mutation and SOD1 mouse models of ALS, the researchers found evidence that all types of cells were producing SOD1—from liver to heart to sensory neurons—but only very specific motor neurons showed evidence of the toxic SOD1. Whereas one motor neuron might show evidence of the toxic SOD1, its neighbor might not. And when Glass and colleagues tracked these motor neurons over time, they found that the presence of toxic SOD1 was essentially a death knell for these motor neurons. Expression of the toxic SOD1 only happened in motor neurons that were destined to die.

Further experiments showed that the toxic SOD1 protein didn’t show signs of misfolding, nor was it necessarily insoluble, as researchers previously thought. As well, when Glass and colleagues looked for this toxic SOD1 protein in non-SOD1 rodent models of ALS and in sporadic ALS patients, they didn’t find any.

Although these two findings appear to contradict each other, in reality, they complement each other. Glass stressed that these studies looked at SOD1 in two very different contexts, studying different types of cells and different subtypes of ALS. “The two studies don’t necessarily speak to the same issue of whether sporadic and familial ALS have common features of SOD1 pathology,” Glass said. “The whole idea that we understand what the toxic form of this protein is remains in question.”

Packard Center Science Director Piera Pasinelli.

Pasinelli adds: “Both studies suggest that, rather than looking for the presence of a misfolded SOD1 as a marker of disease in sporadic ALS patients, scientists need to use different tools to identify potential disease-triggered modifications in SOD1."

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 potentially shared by sporadic and familial ALS may enable researchers to generalize mutant SOD1 models to ALS disease that doesn’t involve SOD1 mutations. As well, understanding how mutant SOD1 leads to ALS may help researchers better understand the disease process regardless of the precise genetic mutation. Lastly, these studies may open the door to subtyping ALS patients based on specific biomarkers.

Carrie Arnold

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The hope is in the science.
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