\ Researchers \ Understanding SOD-1
Some ALS patients (estimates are between 5 and 10 per cent) inherit the disease. Some cases of the familial form of ALS (fALS) have been traced to mutations in the gene for a protein called superoxide dismutase 1 (SOD-1). A variety of mutations of SOD-1 have been identified in patients with fALS, but as there are so few patients with any given type of mutation, it is difficult for researchers to gather statistics about corresponding pathological features, such as the average age of onset or average disease duration.
But Dr. Elizabeth Meiering, an ALS researcher in the Department of Chemistry at the University of Waterloo, has the answer. By creating SOD-1 mutations in culture, she characterizes both the types of mutations that can exist, and their potential connections to actual ALS pathology. Already, Meiering has successfully demonstrated a link between SOD-1 mutations and neuronal aggregates. Normal proteins fold and unfold themselves to bind with other molecules, assembling functional complexes. But mutated SOD-1 proteins have decreased stability, altered rates of folding and unfolding, and a greater propensity to form toxic aggregates in motor neurons.
A variety of SOD-1 mutations can occur at various places on the molecule. Meiering plans to look at different classes of mutations, (for example, some mutations are involved metal-binding, others are charge mutations) and then characterize how the mutants behave and how that may be linked to the disease. “I think it’s valuable to get these proteins and characterize them,” says Meiering. “If they are going to aggregate, and we can see they do, then how does that occur? Do you have to wait for the protein to unfold? Does it have to partially unfold or completely unfold? We don’t know.”
“Quite a lot is known about how superoxide dismutase functions as an enzyme,” says Meiering, “but not about its folding.” One possibility, she says, is that SOD-1 mutations can change the rate of unfolding. “The aggregation properties may be linked to the rate of unfolding of the protein. We can measure the rate of unfolding in real time by placing the protein into unfolding conditions and monitoring protein fluorescence changes as the protein unfolds.” A prevalent form of fALS involves a mutation of the “A4V” protein. “What is interesting,” says Meiering, “is that is a very prevalent mutation, that has very clearly one of the shortest disease durations. This mutant also unfolds particularly quickly, more quickly than the other mutants we looked at. And that makes you wonder, is that going to be linked with the very rapid progression of this disease?”
Using a variety of techniques, including mass spectrometry and electron microscopy, and with the help of funding from the Neuromuscular Research Partnership, Meiering intends to find answers to these questions. Meiering’s work promises advances in our understanding of these mechanisms of ALS, and also new targets for drug therapies. “I want to know exactly what parts of the SOD molecule may become destabilized or unfold, and thereby create a new interface for binding another SOD molecule causing aggregation. If we know what that is then we can try to design inhibitors against aggregation.”
Definitions
mass spectrometry – a mass spectrometer is an instrument that uses the basic magnetic force on a moving charged particle to measure the masses and relative concentrations of atoms and molecules in a sample.
electron microscopy – electron microscopes use electrons rather than visible light to produce magnified images. They are used to view objects smaller than the wavelengths of visible light.
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Understanding SOD-1
Some ALS patients (estimates are between 5 and 10 per cent) inherit the disease. Some cases of the familial form of ALS (fALS) have been traced to mutations in the gene for a protein called superoxide dismutase 1 (SOD-1). A variety of mutations of SOD-1 have been identified in patients with fALS, but as there are so few patients with any given type of mutation, it is difficult for researchers to gather statistics about corresponding pathological features, such as the average age of onset or average disease duration. But Dr. Elizabeth Meiering, an ALS researcher in the Department of Chemistry at the University of Waterloo, has the answer. By creating SOD-1 mutations in culture, she characterizes both the types of mutations that can exist, and their potential connections to actual ALS pathology. Already, Meiering has successfully demonstrated a link between SOD-1 mutations and neuronal aggregates. Normal proteins fold and unfold themselves to bind with other molecules, assembling functional complexes. But mutated SOD-1 proteins have decreased stability, altered rates of folding and unfolding, and a greater propensity to form toxic aggregates in motor neurons.
A variety of SOD-1 mutations can occur at various places on the molecule. Meiering plans to look at different classes of mutations, (for example, some mutations are involved metal-binding, others are charge mutations) and then characterize how the mutants behave and how that may be linked to the disease. “I think it’s valuable to get these proteins and characterize them,” says Meiering. “If they are going to aggregate, and we can see they do, then how does that occur? Do you have to wait for the protein to unfold? Does it have to partially unfold or completely unfold? We don’t know.”
“Quite a lot is known about how superoxide dismutase functions as an enzyme,” says Meiering, “but not about its folding.” One possibility, she says, is that SOD-1 mutations can change the rate of unfolding. “The aggregation properties may be linked to the rate of unfolding of the protein. We can measure the rate of unfolding in real time by placing the protein into unfolding conditions and monitoring protein fluorescence changes as the protein unfolds.” A prevalent form of fALS involves a mutation of the “A4V” protein. “What is interesting,” says Meiering, “is that is a very prevalent mutation, that has very clearly one of the shortest disease durations. This mutant also unfolds particularly quickly, more quickly than the other mutants we looked at. And that makes you wonder, is that going to be linked with the very rapid progression of this disease?”
Using a variety of techniques, including mass spectrometry and electron microscopy, and with the help of funding from the Neuromuscular Research Partnership, Meiering intends to find answers to these questions. Meiering’s work promises advances in our understanding of these mechanisms of ALS, and also new targets for drug therapies. “I want to know exactly what parts of the SOD molecule may become destabilized or unfold, and thereby create a new interface for binding another SOD molecule causing aggregation. If we know what that is then we can try to design inhibitors against aggregation.”
Definitions
mass spectrometry – a mass spectrometer is an instrument that uses the basic magnetic force on a moving charged particle to measure the masses and relative concentrations of atoms and molecules in a sample.
electron microscopy – electron microscopes use electrons rather than visible light to produce magnified images. They are used to view objects smaller than the wavelengths of visible light.
| Posted On: Monday, April 19, 2004 Modified: Monday, April 19, 2004 Category: Researchers Posted By: |