Now, for the first time, cellular biologists at the University of Georgia have developed new tools to study and localize GPIs in living organisms and are discovering a new understanding of how they work in tropical parasites that cause human disease and suffering.
The research was published in the May 9 issue of The FEBS (Federation of European Biochemical Societies) Journal by Kojo Mensa-Wilmot, professor of cellular and molecular biology, and Sandesh Subramanya, a former doctoral student in the department of cellular biology at UGA.
While some GPIs are "attached" to proteins cells, other GPIs are "free," and it is these footloose cellular wanderers that interested Mensa-Wilmot. Until the UGA team developed new molecular tools to study free GPIs in living organisms, their function was unclear at best. Now, new avenues of study could open because of these molecular tools.
Although the term "lipid" is often substituted for "fat," these cell components actually have numerous functions. They are hydrocarbon-containing organic compounds that living cells must have to maintain structure and function. Glycolipids are attached to carbohydrates, and they are involved with cellular energy and also serve as markers for cellular recognition.
The researchers discovered a new function for these glycolipids--they are cleaved in response to cell stress caused by changes in osmotic pressure and relative acidity or alkalinity.
The research by the UGA team is especially important in better understanding the parasite Trypanosoma brucei, which causes human African trypanosomiasis, a disease that affects more than 66 million women, men and children in 36 countries of sub-Saharan Africa. The parasite is transmitted to humans through the bite of the tsetse fly, in which the trypanosome transfers from the mid-gut to the salivary glands where it enters the human bloodstream when the fly bites.
"We found that putting these cells under stress similar to that initially encountered by the trypanosome inside the fly caused the parasites to cleave free GPIs," said Mensa-Wilmot, "and that gives us important information about how the trypanosome cell functions."
The new tools aren't just helpful in understanding GPIs in T. brucei, either. The team found that it works just as well in understanding the parasite Leishmania, which causes another pervasive and terrible tropical disease called Leishmaniasis. This debilitating disease is found is more than 88 countries where a third of a billion people are at risk to contract it.
In the same set of experiments, the researchers discovered a new pathway for protein movement in the trypanosome that may also be found in other cell types including humans. The scientists discovered that proteins can move from a glycosome, an important energy-generating organelle in a trypanosome, to the endoplasmic reticulum where GPIs are made, in response to cell stress.
The human equivalent of a glycosome is a peroxisome, whose malfunction is associated with diseases such as Zellweger Syndrome. According to the National Institute of Neurological Disorders and Stroke, symptoms of this disorder at birth "may include lack of muscle tone and an inability to move. Other symptoms may include unusual facial characteristics, mental retardation, seizures and an inability to suck and/or swallow. Jaundice and gastrointestinal bleeding may also occur."
The new research will open areas for further investigation.
"Before this work in trypanosomes, there was no evidence that we could 'catch' peroxisome proteins moving to the ER" said Mensa-Wilmot. "With better understanding of the process we could begin looking for compounds that may act as drugs by blocking the parasite's ability to respond to extracellular stress."
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