Cellular Communications Breakdown Identified In Inherited Brain Disorder

April 11, 2005

GAINESVILLE, Fla. — A breakdown in brain cell communication may contribute to the most common biochemical cause of mental retardation, University of Florida scientists have discovered.

The process is akin to a baseball game gone bad. Imagine if a pitcher were joined by six players simultaneously winding up on the mound. Crouched behind home plate, the single catcher would soon be overwhelmed. Even if the coach sent in teammates to catch the extra balls, confusion would reign on the field.

UF researchers, writing in the journal Brain, identified an analogous situation in the brains of mice with a version of the hereditary disorder phenylketonuria, or PKU: A flood of an amino acid found in nearly all foods bombards certain brain cells, drowning out their ability to communicate properly and potentially interfering with normal brain development.

Scientists have long known that babies born with PKU lack or are deficient in the enzyme that converts the amino acid phenylalanine into a usable form. The amount of the amino acid in the blood builds to toxic levels, ultimately causing severe brain disorders, including mental retardation and seizures. Researchers have been less clear on precisely how that torrent of phenylalanine interferes with brain function.

“Despite tremendous progress in the understanding of the molecular basis of PKU, the mechanisms of how the brain is negatively affected by high levels of phenylalanine has not been known,” said Anatoly Martynyuk, an assistant professor of anesthesiology and neuroscience at UF’s College of Medicine and the McKnight Brain Institute. “This is a new and original approach to explain the cellular mechanisms of brain dysfunction in PKU.”

The findings could someday lead to a treatment for the disease in people and provide insight into other neurological disorders with similar symptoms, Martynyuk said.

Every state screens newborns for PKU. Those with the condition are restricted to an arduous all-liquid diet that eliminates or greatly reduces protein intake, at least through adolescence and possibly throughout their lives. Caught early, brain damage can be avoided and people with the condition can lead normal lives, except for having to adhere to a protein-free liquid diet.

UF researchers discovered that in the brains of mice with PKU, levels of phenylalanine soar to six times higher than levels found in healthy mice. The excess phenylalanine interferes with a key brain cell chemical messenger, glutamate, which plays a crucial role in brain development and function.

The changes in that cellular communication system may at least partially explain the brain disorders associated with PKU, Martynyuk said.

Martynyuk said UF researchers are now examining how the process contributes to seizures in patients with PKU who are not treated with a special diet.

“Based on our findings, we hypothesize that the changes in the brain can be caused not only by higher levels of phenylalanine, but also by withdrawal of phenylalanine,” Martynyuk said. “For example, sequential decreases in phenylalanine levels caused by variations in diet will facilitate glutamate system activity in the brain and can destabilize the entire system. In such conditions, seizures are likely.”

UF researchers said related research suggests phenylalanine and its derivatives might someday be used to treat other brain disorders in which an abnormal glutamate system plays a role, such as stroke and schizophrenia.