Researchers Find Production Point Of Key Protein In Fragile X Syndrome

May 13, 1997

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.

University of Illinois at Urbana-Champaign

Related Brain Articles from Brightsurf:

Glioblastoma nanomedicine crosses into brain in mice, eradicates recurring brain cancer
A new synthetic protein nanoparticle capable of slipping past the nearly impermeable blood-brain barrier in mice could deliver cancer-killing drugs directly to malignant brain tumors, new research from the University of Michigan shows.

Children with asymptomatic brain bleeds as newborns show normal brain development at age 2
A study by UNC researchers finds that neurodevelopmental scores and gray matter volumes at age two years did not differ between children who had MRI-confirmed asymptomatic subdural hemorrhages when they were neonates, compared to children with no history of subdural hemorrhage.

New model of human brain 'conversations' could inform research on brain disease, cognition
A team of Indiana University neuroscientists has built a new model of human brain networks that sheds light on how the brain functions.

Human brain size gene triggers bigger brain in monkeys
Dresden and Japanese researchers show that a human-specific gene causes a larger neocortex in the common marmoset, a non-human primate.

Unique insight into development of the human brain: Model of the early embryonic brain
Stem cell researchers from the University of Copenhagen have designed a model of an early embryonic brain.

An optical brain-to-brain interface supports information exchange for locomotion control
Chinese researchers established an optical BtBI that supports rapid information transmission for precise locomotion control, thus providing a proof-of-principle demonstration of fast BtBI for real-time behavioral control.

Transplanting human nerve cells into a mouse brain reveals how they wire into brain circuits
A team of researchers led by Pierre Vanderhaeghen and Vincent Bonin (VIB-KU Leuven, Université libre de Bruxelles and NERF) showed how human nerve cells can develop at their own pace, and form highly precise connections with the surrounding mouse brain cells.

Brain scans reveal how the human brain compensates when one hemisphere is removed
Researchers studying six adults who had one of their brain hemispheres removed during childhood to reduce epileptic seizures found that the remaining half of the brain formed unusually strong connections between different functional brain networks, which potentially help the body to function as if the brain were intact.

Alcohol byproduct contributes to brain chemistry changes in specific brain regions
Study of mouse models provides clear implications for new targets to treat alcohol use disorder and fetal alcohol syndrome.

Scientists predict the areas of the brain to stimulate transitions between different brain states
Using a computer model of the brain, Gustavo Deco, director of the Center for Brain and Cognition, and Josephine Cruzat, a member of his team, together with a group of international collaborators, have developed an innovative method published in Proceedings of the National Academy of Sciences on Sept.

Read More: Brain News and Brain Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to