Fragile X affects one in 4,000 boys and one in 6,000 girls. It is caused by a mutation in the fragile x mental retardation 1 gene (FMR1)—located on the X sex chromosome— that results in the loss of the fragile x mental retardation protein (FMRP). The resulting illness is characterized by hyperactivity, attention deficit, repetitive behavior, anxiety and cognitive difficulties ranging from learning disability to mental retardation.
Previous studies of fragile X show that nerve cells in the cortex (the outermost layer of the brain) of both patients and knockout mice have dendrites (rootlike projections that nerve cells use to receive electrical signals from peers) with a greater number of branches. These extra shoots are thin, stubby, immature and less functional than normal dendrites, causing poor transmission among neurons across synapses (the spaces between nerve cells).
When studying the formation of dendrites for a 2004 paper, Mansuo Hayashi, a research affiliate in M.I.T.'s Picower Institute for Learning and Memory, discovered that these structures could be strengthened and altered to transmit information more efficiently by inhibiting nerve cell production of the enzyme called p21-activated kinase (PAK). PAK regulates actin, another protein, which shapes parts of the cell (including the dendrites). When PAK is inhibited, more actin is manufactured and the dendrites are able to properly mature.
In the current study, Hayashi led a team that worked with "double mutant" mice. First, the researchers mutated the FMR1 so that the mice would lack FMRP protein and thus show symptoms of fragile X. A second mutation to the gene that codes for PAK caused the mouse's cells in the forebrain to stop producing the enzyme at three weeks after birth. "When these two mutants were crossed together, [the mice] were normal," says senior study author Susumu Tonegawa, a professor of neuroscience and biology at Picower.
Not only did the dendrites of the fragile X–afflicted mice become more robust and efficient, but researchers report that several of the behavioral symptoms associated with the disorder also abated: Double mutant mice behaved more like normal mice than like those with fragile X.
William Greenough, a professor of psychology at the University of Illinois at Urbana-Champaign, says that the study demonstrates the long-term potential of gene therapy. "I am impressed by the kinds of different symptoms … that seem to be under [the] governance of this single signaling pathway," he says. "It seems to affect everything from neuronal morphology (or shape) to behavior that may or may not be coupled to that morphology."
Tonegawa says that the results may pave the way to a possible new molecular target for new drugs. "If you take a fragile X patient and feed them or inject them with a compound that will inhibit their own endogenous PAK enzyme," he says, "it may reduce the fragile X symptoms." He notes that a significant finding of the study is that the effects of fragile X—which is typically diagnosed only after a child shows marked developmental delays, such as being late to crawl, walk or talk—could be reversed at the onset.