Genetics and Aging.
Martha Stipanuk may have found a genetic predisposition that causes rheumatoid arthritis and several degenerative neurological diseases to be more severe or to progress more rapidly in some people than in others. The results of her research could lead to better treatment of these diseases, either through dietary supplements or even by altering how certain human genes are regulated.
Stipanuk, professor of nutritional sciences, is studying the genetic basis for this predisposition in how people process cysteine, a sulfur-containing amino acid found in most food proteins. "We depend on sulfur amino acids as a source of taurine and sulfate," Stipanuk says, "because we don't get much preformed taurine or sulfate in our diet." Although cysteine is essential for the synthesis of proteins and glutathione, as well as for being degraded to form sulfate and taurine, very little is known about just how cysteine metabolism works, she says. "It is an area that seemed under-researched and ripe for somebody to pursue consistently."
Stipanuk may have caught the object of her pursuit.
"We have defined the pathways involved in cysteine metabolism, we're finding out how those pathways are regulated, and we have identified the key enzymes involved in the regulation of those path ways," she explains. "Now we're investigating what determines how fast cysteine is metabolized-when is it degraded quickly, and when do we conserve it? If you don't have much cysteine, your body wants to conserve it so it can be used for synthesis of protein or glutathione." But too much cysteine, on the other hand, is toxic to cells, particularly neurons, so the body needs to get rid of it quickly if there is an abundance."
Stipanuk's studies have led her to focus on one particular enzyme: cysteine dioxygenase, or CDO, which "undergoes a very robust regulatory response," she says. CDO is found mainly in the liver, and it shows strong regulation in response to diet: when animals are fed a very low protein diet, CDO levels in the liver are almost nonexistent; once the protein is increased to around a normal level, "you get a very strong increase in the amount of this enzyme present," she says. "As you go from low to excess levels, you get a 200-fold increase in the amount of this enzyme, which is a big, big increase. Thus, the capacity of the liver to degrade cysteine to sulfate is immensely increased. Normally, when you're looking at enzyme regulation, you're looking at a two- or threefold increase, and even that's big."
Apparently, the body picks the least energy-efficient way of regulating the amount of CDO. A cell will go through the whole process of making the protein, Stipanuk says, and then if it doesn't need the protein, it just breaks it down. Although costly in terms of energy expenditure, this method ensures that the protein is always being made and hence can rapidly become available to do its job. "We think cysteine itself, or some molecule closely related to it, stabilizes the protein and prevents it from being broken down when cysteine is abundant and the enzyme is needed."
Stipanuk believes that some people's bodies may make more CDO than others. Some individuals have high ratios of cysteine to sulfate in their plasma and tissues, which indicates that, although they may have adequate levels of cysteine, they're not able to properly degrade cysteine to sulfate. There is evidence that the impaired cysteine degradation is due to low levels of CDO. The phenomenon suggests a genetic variability in the population.
"The most striking example of this in ability to convert cysteine to sulfate is found in people with rheumatoid arthritis," Stipanuk says. "A significant number of sufferers have altered ratios of cysteine to sulfate and very low concentrations of sulfate in the synovial fluid in the joints. We don't know what the connection is, but I think there may be some genetic variability in CDO that doesn't necessarily cause rheumatoid arthritis but is associated with a greater likelihood for developing the disease and for its rapid progression."
Other degenerative neurological diseases such as Parkinson's disease, motor neuron disease, and possibly Alzheimer's disease also seem to be associated with problems in processing cysteine, Stipanuk says. "If these diseases have anything to do with cysteine degradation, they might be treated by altering the regulation of the CDO gene in some way." Altering the amounts of cysteine, sulfate, and taurine in the diet may be another approach to the problem.
Stipanuk credits ongoing genomics research for providing the era of knowledge in which she can do her work. "The research others have been doing provided the genetic sequence for the CDO enzyme," she says. "Without knowing the sequence, we couldn't clone the gene. Using the sequence data others had obtained for the rat and human genes, we were able to clone the mouse CDO gene. No one had done that before." The cloned mouse gene is being used to create transgenic mice--laboratory mice that have a piece of DNA inserted as a transgene or are bred with certain genes "knocked out" so that the resulting effects can be studied.
Developing a transgenic mouse model "will facilitate both basic research and understanding of some disease and gene connections," Stipanuk says. "Deleting the gene for CDO on one or both chromosomes will give us mice with a range of CDO activities. Clinical examination of these mice and their metabolic profiles should provide insight into the association between cysteine metabolism and chronic diseases. We'll probably work with people at the Vet College to assess the animals and see what happens as a result of knocking out the CDO gene. The potential connection between diseases and the variability in expression of this gene in the human population is exciting."
Stipanuk has funding from the National Institutes of Health to work on aspects of cysteine metabolism and much of her research on CDO. The transgenic mouse work is being funded by the National Institute of Aging as part of a program designed "to encourage people working in different areas to relate their work to aging," she explains.
Stipanuk hopes that working with mice will have direct connections with the study of cysteine metabolism in the human. She speculates that the upcoming questions may be: How do you go about screening humans for CDO activity, and what aspects might be different in humans and in mice?
"I'm hoping that working with the mouse model will enable us to detect some metabolic abnormalities that will allow us to screen human populations in a noninvasive way."
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|Date:||Mar 22, 2001|
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