CHAMPAIGN, Ill. - Efforts to understand the mechanism for the most common cause of genetically inherited mental impairment in males have been bolstered by researchers who have found that the synthesis of a key protein occurs in an unexpected location in the brain.
Scientists from four universities report that the fragile X protein is produced in synapses junctions through which nerve cells communicate. The discovery is backed by a second study that shows when the gene that initially receives the fragile X protein is "knocked out" of the X chromosome, halting the protein's production within synapses, then normal brain development appears to stop at an early stage.
Findings of the studies conducted at the University of Illinois will appear in the May 13 Proceedings of the National Academy of Sciences. The research was funded primarily by the National Institute of Mental Health and the FRAXA Research Foundation, a non-profit organization run by parents and medical professionals.
"The fragile X protein that is produced at synapses appears to be essential to normal synapse maturation and development of the wiring diagram of the brain," said lead researcher William T. Greenough of the U. of I. psychology department and the U. of I. Beckman Institute for Advanced Science and Technology.
There is no cure for fragile X syndrome, which is caused by the genetic inability to normally produce the fragile X protein. "Fragile X" refers to the broken appearance of the X chromosome -- half the chromosome pair that determines sex -- when cells are cultured under specific conditions. The gene was found in 1969, but its relationship to mental retardation was not understood. It was sequenced and named the Fragile X Mental Retardation Gene in 1991, but its mechanisms remained a mystery.
The Fragile X Mental Retardation Gene is carried by mothers and passed on to sons. One in every 1,000 women is believed to carry the defective gene; about one in every 2,000 males is affected. Telling physical features include a long narrow face and/or prominent ears, jaw and forehead. Impairment ranges from severe retardation to slightly below normal intelligence.
The X chromosome contains many genes. The fragile X gene contains the code for the fragile X mental retardation protein. That code is transferred from the gene into messenger RNA and transported to a distant synapse where it serves as a template for producing the fragile X protein, said Greenough, who also is a professor of psychiatry and of cell and structural biology.
"The function of the fragile X protein, and the reason that people who could not make the protein exhibit developmental delay, has not been known," he said. "This finding points to a mechanism of action of the protein that may account for the mental retardation."
Greenough's team studied rats to determine the synapse location for the protein's production. The findings of abnormal nerve cells resulted from studies of transgenic mice that cannot produce the fragile X protein. Previous research based on autopsies of human victims had shown immature synapse formation, but that work had not revealed the impairment of the synapse pruning process, in which excess synapses are deleted.
While stressing that new treatments for fragile X syndrome won't immediately result from the findings, Greenough said, "The knowledge allows us to focus on a particular aspect of the brain and its development in efforts to better understand the disorder."
"It had been known from studies of mice, rats, cats, monkeys and humans that the developing brain overproduces synapses through which nerve cells communicate," he said.
"Subsequently, experience, by activating nerve cells, determines which synapses become mature and stable and which synapses are pruned," Greenough said. "These findings implicate the production of the fragile X protein at synapses in the stabilization and pruning process. It also may be that the synthesis is involved in later processes of adult learning and memory."
U. of I. coauthors of the studies were Greenough; Ivan Jeanne Weiler and Anna Y. Klintsova, researchers at the Beckman Institute; Scott A. Irwin, a doctoral student of neuroscience and medicine in the medical scholars program; graduate neuroscience and Beckman researchers Anthony D. Brazelton and Thomas A. Comery; and undergraduate assistants Bindu Patel and Jennifer B. Harris.
Other scientists were Corrine M. Spencer, Kevin Miyashiro and James Eberwine of the University of Pennsylvania Medical Center in Philadelphia, who identified which messenger RNAs were involved. Patrick J. Willems of the University of Antwerp, Belgium, and Ben A. Oostra of Erasmus University in the Netherlands developed the transgenic mice for the project.