New approaches to preventing birth defects from a rare metabolic disorder could result from research completed at Washington University School of Medicine in St. Louis. The findings also may have implications for patients with neurodegenerative diseases such as Parkinson’s.
To learn more about how glucose affects human development, Mary Carayannopoulos, Ph.D., instructor in pediatrics, developed the first vertebrate model of glucose homeostasis and embryonic development using the zebrafish. Their transparent embryos develop similarly to humans, except that they grow outside of the mother’s body, where development can be more easily observed. The model provides the foundation for and insight into the roles of nutrition and genetics in human birth defects.
Carayannopoulos used the zebrafish model to study Glut1 deficiency. Glut1 is a protein that transports glucose in cerebrospinal fluid to the brain. Glut1 deficiency syndrome in humans is linked to microcephaly, epilepsy, developmental delays and other neurologic abnormalities.
Results of the study appear in the June issue of the Journal of Biological Chemistry, but are available now online. Penny J. Jensen, Ph.D., staff scientist in the Department of Pediatrics, was lead author of the study.
Carayannopoulos lowered Glut1 levels in the zebrafish embryo. Over 72 hours of observing the developing fish, she found that Glut1 deficiency led to cell death in the brain, which uses glucose as its energy source. When injecting the zebrafish with another protein, Bad, which normally activates cell death, the Glut1 and Bad seemed to cancel each other out, correcting brain defects and promoting cell survival.
“Our biggest finding was that the level of glucose a cell senses tells the cell to live or die,” says Carayannopoulos. “If we can understand the mechanism by which cells sense glucose in conditions where glucose levels are altered, we might be able to prevent cell death and design therapeutics that would interfere with the cell death pathway.”
The brain develops abnormally in the absence of Glut1, says collaborator Jonathan Gitlin, M.D., the Helene B. Roberson Professor of Pediatrics, professor of genetics and of pathology and immunology at the School of Medicine, and director of genetics and genomic medicine at St. Louis Children’s Hospital.
“Mary’s elegant work broadens our appreciation of the mechanisms involved in abnormal brain development and suggests a need for further study of glucose pathways in children with such defects,” Gitlin says. “Furthermore, her findings with the Bad protein suggest new avenues for developing drugs that might prevent neurodegeneration, not only in the developing brain but also in diseases like Parkinson’s, where there may also be a previously unappreciated impairment in glucose metabolism.”
Although only about 100 patients worldwide have been found to have Glut1 deficiency syndrome since 1991, the discovery is a step toward progress in understanding how glucose metabolism affects brain development.
“Whenever we make a small discovery, we see incredibly broad possibilities,” Gitlin says. “It gives us avenues for exploration into new areas that will eventually lead back to a patient’s bedside.”
Currently, the only treatment for Glut1 deficiency syndrome is a ketogenic diet, which is very high in fats and low in carbohydrates and makes the body burn fat for energy instead of glucose.
Washington University School of Medicine’s full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.
The research was supported by a grant from the National Institutes of Health.
Jensen P., Gitlin J., and Carayannopoulos M. Glut1 deficiency links nutrient availability and apoptosis during embryonic development. Journal of Biological Chemistry. June 2006.