MIT researchers working with mice have reversed the symptoms of fragile X syndrome, the most common inherited form of mental retardation in humans. Fragile X affects about 1 in 4,000 boys and 1 in 6,000 girls; it also accounts for about 4 percent of autism cases. There is no treatment.
“The study offers a totally new molecular target for developing fragile X drugs,” says Susumu Tonegawa, Picower Professor of Biology and Neuroscience.
Named for the X chromosome where the disease mutation lies, fragile X can cause learning disabilities, delayed language acquisition, impaired social interaction, and senseless repetitive behaviors. Symptoms tend to be more severe in males; females with the mutation may be of normal intelligence.
Tonegawa and former postdoc Mansuo Hayashi, now at Merck Research Laboratories, found that inhibiting an enzyme called PAK reversed symptoms in mice at the cellular and behavioral levels. The behavioral and learning disabilities in humans and mice with fragile X seem to be caused by structural defects in dendrites, neurons’ signaling arms. Dendrites communicate through bumps called spines; dendrites affected by fragile X don’t communicate well because they have too many spines, and the spines are elongated and thin. Inhibiting PAK reduced the number of spines and caused them to assume more normal shapes; behavioral and cognitive problems disappeared.
The mice were genetically engineered to produce large amounts of nonfunctioning PAK three weeks after birth. This overwhelmed the activity of the functioning PAK, effectively inhibiting the enzyme. By waiting three weeks to inhibit PAK, the study showed that symptom reversal is possible even after fragile X begins to progress. Researchers can now test compounds that inhibit PAK and develop them for therapeutic use.