A disease in worms that resembles a severe form of human muscular dystrophy appears to stem from a problem in transporting a critical chemical from nerves to muscles. The finding has fueled suspicions that similar problems may occur in people with muscular dystrophy, although researchers caution that they don't have direct evidence of that yet.
For muscles to contract, nerve endings touching muscle must release a chemical called acetylcholine. Defects in acetylcholine transmission have been found in some muscle diseases, including the autoimmune disorder myasthenia gravis. Consequently, researchers have suspected that the transmission or breakdown of acetylcholine may also be faulty in muscular dystrophies.
Neuroscientist and geneticist Steven McIntire of the University of California, San Francisco, and his colleagues discovered a possible acetylcholine connection partly by accident. They had been working with a worm model of Duchenne muscular dystrophy, a severe form of the disease that strikes young boys and is caused by mutations in the gene that encodes the dystrophin protein. While screening hundreds of mutant worms for those with locomotion defects, the group identified a strain that looked identical to the typical worm model of Duchenne muscular dystrophy. Like the dystrophin-defective animals, the new mutants couldn't control their muscles when they slithered backward. McIntire, intrigued, decided to investigate further.
He found that the worms had mutations in a previously unidentified gene, which was named snf-6. That gene, McIntire's team discovered, encodes a protein that transports acetylcholine from nerves to muscles, the first such transporter discovered. The worms seemed to need that transporter to function when they were moving rapidly. In the mutant animals, the transporter was malfunctioning. Furthermore, although the original muscular dystrophy worms didn't have mutations in snf-6, they did lack the transporter protein at some sites where nerves abutted muscles, the researchers report in the 19 August issue of Nature.
The paper is "an important milestone," says Laurent Segalat, a geneticist at the University of Lyon, France, because it finally links the worm muscular dystrophy model with defects in acetylcholine transport and breakdown. Judy Anderson, a muscular dystrophy expert at the University of Manitoba in Winnipeg, Canada, adds that evidence for acetylcholine defects in human muscular dystrophy has been contradictory over the years, but if this preliminary finding holds up in mice and humans, it could pave the way for new drug targets.