It's a chicken and egg question. Where do the infectious protein particles called prions come from? Essentially clumps of misfolded proteins, prions cause neurodegenerative disorders, such as mad cow/Creutzfeldt-Jakob disease, in humans and animals. Research in fungi has suggested that sometimes prions can also help cells adapt to different conditions. Prions trigger the misfolding and aggregation of their properly folded protein counterparts, but they usually need some kind of "seed" to get started.
Scientists have studied a yeast protein called Lsb2 that can promote spontaneous prion formation. This unstable, short-lived protein is strongly induced by cellular stresses such as heat. Lsb2's properties also illustrate how cells have developed ways to control and regulate prion formation. The results are published in the July 22 issue of the journal Molecular Cell.
The study was conducted by members of the Center for Nanobiology of the Macromolecular Assembly Disorders (NanoMAD) which is made up of scientists from the Georgia Institute of Technology and Emory University. Scientists from the National Institues of Health and the University of Illinois at Chicago also contributed to the study. The first author is senior associate Tatiana Chernova, PhD at Emory.
The aggregated, or amyloid, forms of proteins connected with several other neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntingtonâs can, in some circumstances, act like prions. So the findings provide insight into how the ways that cells deal with stress might lead to poisonous protein aggregation in human diseases.
"A direct human homolog of Lsb2 doesnât exist, but there may be a protein that performs the same function," said Keith Wilkinson, professor of biochemistry at Emory University School of Medicine. "The mechanism may say more about other types of protein aggregates than about classical prions in humans. This mechanism of seeding and growth may be more important for aggregate formation in diseases such as Huntington's."
Lsb2 does not appear to form stable prions by itself. Rather, it seems to bind to and encourage the aggregation of another protein, Sup35, which does form prions.
"Our model is that stress induces high levels of Lsb2, which allows the accumulation of misfolded prion proteins," Wilkinson said. "Lsb2 protects enough of these newborn prion particles from the quality control machinery for a few of them to get out."
In continuation of previous research by Yury Chernoff, director of NanoMAD and professor in the School of Biology at Georgia Tech, the new data also show that in addition to promoting new prions, Lsb2 strengthens existing prions during stress.
"Little is known about physiological and environmental conditions influencing amyloid diseases in humans," said Chernoff. "Therefore, prophylactic measures, which could end up being more effective than therapies, are essentially non-existant. We hope that yeast model will help to fill this gap."
The research was supported by the National Institutes of Health.
Written by: Emory University and the Georgia Institute of Technology
It's a chicken and egg question. Where do the infectious protein particles called prions come from? Essentially clumps of misfolded proteins, prions cause neurodegenerative disorders, such as mad cow/Creutzfeldt-Jakob disease, in humans and animals. Research in fungi has suggested that sometimes prions can also help cells adapt to different conditions. Prions trigger the misfolding and aggregation of their properly folded protein counterparts, but they usually need some kind of "seed" to get started.
Scientists have studied a yeast protein called Lsb2 that can promote spontaneous prion formation. This unstable, short-lived protein is strongly induced by cellular stresses such as heat. Lsb2's properties also illustrate how cells have developed ways to control and regulate prion formation. The results are published in the July 22 issue of the journal Molecular Cell.
The study was conducted by members of the Center for Nanobiology of the Macromolecular Assembly Disorders (NanoMAD) which is made up of scientists from the Georgia Institute of Technology and Emory University. Scientists from the National Institues of Health and the University of Illinois at Chicago also contributed to the study. The first author is senior associate Tatiana Chernova, PhD at Emory.
The aggregated, or amyloid, forms of proteins connected with several other neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntingtonâs can, in some circumstances, act like prions. So the findings provide insight into how the ways that cells deal with stress might lead to poisonous protein aggregation in human diseases.
"A direct human homolog of Lsb2 doesnât exist, but there may be a protein that performs the same function," said Keith Wilkinson, professor of biochemistry at Emory University School of Medicine. "The mechanism may say more about other types of protein aggregates than about classical prions in humans. This mechanism of seeding and growth may be more important for aggregate formation in diseases such as Huntington's."
Lsb2 does not appear to form stable prions by itself. Rather, it seems to bind to and encourage the aggregation of another protein, Sup35, which does form prions.
"Our model is that stress induces high levels of Lsb2, which allows the accumulation of misfolded prion proteins," Wilkinson said. "Lsb2 protects enough of these newborn prion particles from the quality control machinery for a few of them to get out."
In continuation of previous research by Yury Chernoff, director of NanoMAD and professor in the School of Biology at Georgia Tech, the new data also show that in addition to promoting new prions, Lsb2 strengthens existing prions during stress.
"Little is known about physiological and environmental conditions influencing amyloid diseases in humans," said Chernoff. "Therefore, prophylactic measures, which could end up being more effective than therapies, are essentially non-existant. We hope that yeast model will help to fill this gap."
The research was supported by the National Institutes of Health.
Written by: Emory University and the Georgia Institute of Technology
Dr. Megan Cole, a postdoctoral associate in Prof. Gaucher's group in the School of Biology, was awarded a Ruth L. Kirschstein National Research Service Award (NRSA). The NRSA is a competitive award offered through the National Institutes of Health (NIH) and provides three years of support to promising applicants with the potential to become productive, independent investigators in biomedical, behavioral or clinical research areas. This is the first postdoctoral NRSA awarded to a postdoc in the School of Biology at Georgia Tech. Dr. Cole will use computational and experimental methods to modify protein translation machinery with potentially significant impacts on the field of synthetic biology.
Dr. Megan Cole, a postdoctoral associate in Prof. Gaucher's group in the School of Biology, was awarded a Ruth L. Kirschstein National Research Service Award (NRSA). The NRSA is a competitive award offered through the National Institutes of Health (NIH) and provides three years of support to promising applicants with the potential to become productive, independent investigators in biomedical, behavioral or clinical research areas. This is the first postdoctoral NRSA awarded to a postdoc in the School of Biology at Georgia Tech. Dr. Cole will use computational and experimental methods to modify protein translation machinery with potentially significant impacts on the field of synthetic biology.
Research Horizons, July 09 - Unlike many cancer biology researchers who investigate general processes underlying many cancers, John McDonald focuses his investigations broadly on one type of cancer - ovarian.
Ovarian cancer is the most lethal gynecological cancer, with the American Cancer Society predicting that in the United States alone each year, more than 20,000 women will be diagnosed with ovarian cancer and 16,000 will die from it.
"Ovarian cancer is called the silent killer because by the time symptoms arise and it's detected, it has typically spread throughout the body," says McDonald, chief scientist of the Ovarian Cancer Institute and associate dean for biology development in the School of Biology. "Our laboratory takes an integrated approach to studying ovarian cancer by investigating its causes, establishing accurate and reliable diagnostic tests, and developing novel and effective therapies."
One focus of McDonald's research is to determine how cancer cells develop in the ovaries. While it is estimated that up to 90 percent of ovarian carcinomas are derived from ovarian surface epithelial cells â" cells that create the thin layer of tissue that covers the ovaries â" the behavior of these cells differs from other epithelial-derived carcinomas because they become more specialized as malignancy progresses.
To investigate this behavior in more detail, McDonald and Nathan Bowen, a research scientist and Georgia Cancer Coalition Distinguished Cancer Scholar, compared the gene expression profiles of ovarian surface epithelial cells isolated from the surface of healthy ovaries with those of malignant ovarian tumors collected by the Ovarian Cancer Institute.
The results showed that more than 2,000 genes were expressed at significantly different levels in the two sample types. Genes associated with adult stem cell maintenance were expressed at a much higher level in the cells isolated from healthy ovaries.
"We found that changes in the expression of genes involved in maintaining the inertness and stem cell nature of epithelial surface ovarian cells may be instrumental in the initiation and development of ovarian cancer," explains McDonald.
The results also showed that the surface of the ovary exhibits the characteristics of an adult stem cell niche, which is a protected environment where stem cells remain inactive until a signal triggers their cell cycle and they differentiate.
Expanding on these results, McDonald, Bowen and postdoctoral fellows Roman Mezencev and Lijuan Wang are currently examining the sensitivity of ovarian cancer stem cells and differentiated cancer cells to existing chemotherapy agents.
"The preliminary results indicate that existing chemotherapy agents may effectively kill cancer cells but not touch these cancer stem cells, which could be why ovarian tumors and other cancers frequently recur," adds McDonald.
This work was supported by the Ovarian Cancer Institute, Georgia Cancer Coalition, Golfers Against Cancer Foundation, Ovarian Cycle Foundation, Robinson Family Foundation and Deborah Nash Harris Foundation.
By Abby Vogel
Photo By Gary Meek
Research Horizons, July 09 - Unlike many cancer biology researchers who investigate general processes underlying many cancers, John McDonald focuses his investigations broadly on one type of cancer - ovarian.
Ovarian cancer is the most lethal gynecological cancer, with the American Cancer Society predicting that in the United States alone each year, more than 20,000 women will be diagnosed with ovarian cancer and 16,000 will die from it.
"Ovarian cancer is called the silent killer because by the time symptoms arise and it's detected, it has typically spread throughout the body," says McDonald, chief scientist of the Ovarian Cancer Institute and associate dean for biology development in the School of Biology. "Our laboratory takes an integrated approach to studying ovarian cancer by investigating its causes, establishing accurate and reliable diagnostic tests, and developing novel and effective therapies."
One focus of McDonald's research is to determine how cancer cells develop in the ovaries. While it is estimated that up to 90 percent of ovarian carcinomas are derived from ovarian surface epithelial cells â" cells that create the thin layer of tissue that covers the ovaries â" the behavior of these cells differs from other epithelial-derived carcinomas because they become more specialized as malignancy progresses.
To investigate this behavior in more detail, McDonald and Nathan Bowen, a research scientist and Georgia Cancer Coalition Distinguished Cancer Scholar, compared the gene expression profiles of ovarian surface epithelial cells isolated from the surface of healthy ovaries with those of malignant ovarian tumors collected by the Ovarian Cancer Institute.
The results showed that more than 2,000 genes were expressed at significantly different levels in the two sample types. Genes associated with adult stem cell maintenance were expressed at a much higher level in the cells isolated from healthy ovaries.
"We found that changes in the expression of genes involved in maintaining the inertness and stem cell nature of epithelial surface ovarian cells may be instrumental in the initiation and development of ovarian cancer," explains McDonald.
The results also showed that the surface of the ovary exhibits the characteristics of an adult stem cell niche, which is a protected environment where stem cells remain inactive until a signal triggers their cell cycle and they differentiate.
Expanding on these results, McDonald, Bowen and postdoctoral fellows Roman Mezencev and Lijuan Wang are currently examining the sensitivity of ovarian cancer stem cells and differentiated cancer cells to existing chemotherapy agents.
"The preliminary results indicate that existing chemotherapy agents may effectively kill cancer cells but not touch these cancer stem cells, which could be why ovarian tumors and other cancers frequently recur," adds McDonald.
This work was supported by the Ovarian Cancer Institute, Georgia Cancer Coalition, Golfers Against Cancer Foundation, Ovarian Cycle Foundation, Robinson Family Foundation and Deborah Nash Harris Foundation.
By Abby Vogel
Photo By Gary Meek
PhD student Shandra Justicia has been selected to receive the prestigious American Society for Microbiology (ASM) Robert D. Watkins Graduate Fellowship. ASM's Robert D. Watkins Graduate Fellowship program is highly competitive, and is designed to increase the number of doctoral degrees awarded to members of underrepresented groups. The Robert D. Watkins Graduate Fellowship provides students with a stipend for three years, as well as travel to and accommodations at the annual ASM General Meetings and a visit to the ASM Kadner Institute one time during the three-year tenure of the fellowship.
Shandra Justicia received a dual degree in Industrial Biotechnology and Chemistry from the University of Puerto Rico at Mayagüez. Justicia entered the School of Biology's graduate program in Fall 2007, and is in the laboratory of Dr. Frank Löffler. Her research focuses on microorganisms that can be used in bioremediation, with a particular focus on microbes that can detoxify chlorinated methanes. These compounds have been widely used as solvents and reagents, and are widespread groundwater contaminants, posing risks to human and ecosystem health.
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