Scientists Find First Protein In Central Nervous System Junctions

November 12, 1998

St. Louis, Nov. 13 -- Scientists have identified the first protein needed for synapse formation in the central nervous system. Synapses are connections between cells that make the nervous system function.

Due to a bizarre twist of evolution, the protein also appears essential for using a trace element called molybdenum.

When the protein is missing, mice display symptoms of two life-threatening human diseases. In one, stiff baby syndrome, some synapses in the spinal cord fail to function properly. In the other, molybdenum cofactor deficiency, cells can't make proper use of molybdenum.

"This is an amazing illustration of how wacky nature can be," says Joshua R. Sanes, Ph.D., a neurobiology professor at Washington University School of Medicine in St. Louis. One of his postdoctoral fellows, Guoping Feng, Ph.D., and Hartmut Tintrup, a graduate student from Heinrich Betz's lab at the Max-Planck Institute for Brain Research in Frankfurt, Germany, are first authors of the paper, which appears in the Nov. 13 issue of Science.

Betz and colleagues discovered the protein, gephyrin, in 1982, isolating it from the spinal cord and brain. They named it after the Greek word for "bridge" because they thought it might connect nerve cell receptors to the cell's internal skeleton, anchoring them in the right place to receive messages from other nerve cells.

A chemical called glycine delivers these messages at some synapses in the spinal cord, damping the activity of recipient cells. It therefore plays a tug-of-war with other chemicals that stimulate the same nerve cells, keeping those cells in balance. When the nerve cells fail to receive glycine signals, they overreact to positive signals and in turn overstimulate muscles. Strychnine, which is commonly used as a rat poison, induces spastic paralysis by blocking receptors for glycine. People with faulty glycine receptors are extremely sick because of excessive contraction of their muscles.

For the past 20 years, Sanes has studied the synapse between nerve cells and muscle, the neuromuscular junction. One of the synaptic proteins his group discovered links stimulatory receptors to the cellular skeleton. He therefore wanted to explore the role of gephyrin, which appeared to play a corresponding role in the central nervous system.

To obtain definitive proof of function, Feng and Tintrup inactivated the gephyrin gene in mice and studied the outcome. Mice that lacked both copies of the gene failed to cluster the glycine receptors in their spinal cord neurons. They also extended their bodies and were spastic, dying within a day of birth. These symptoms were very similar to those induced in mice by strychnine and would be expected if lack of gephyrin sabotages the development of inhibitory synapses.

"The main conclusion of the paper is that we have identified, for the first time, a protein that is absolutely essential for the development of a central nervous system synapse," Sanes says. "This genetic approach gives you as close as you can get to a truly definitive proof of what a protein is doing."

Betz also had determined that gephyrin's amino acid content was surprisingly similar to that of bacterial proteins that process molybdenum, which is required by all living cells. Molybdenum, a heavy metal, makes certain enzymes work. "Reading the literature, I also realized that the symptoms of our mutant mice were very similar to those of molybdenum cofactor deficiency disease," Feng says. "Those patients have seizures early in life, and they extend their body and limb muscles just like our gephyrin mutants. They also can't suckle milk, and our mice had difficulty feeding."

Feng and Tintrup performed the definitive test for molybdenum cofactor deficiency by assaying liver and intestine for two unrelated molybdenum-requiring enzymes. Neither was active in the gephyrin-deficient mice. The researchers also showed that the spasticity of these mutants really did result from a lack of inhibitory synapses in the spinal cord as well as from molybdenum cofactor deficiency.

"We came to the remarkable conclusion that this protein is required for making inhibitory synapses in the spinal cord and also is required to use molybdenum in all tissues," Sanes says. "So it looks to us as if gephyrin has two seemingly unrelated functions - an amazing example of nature using whatever works to get the job done."
Feng G, Tintrup H, Kirsch J, Nichol MC, Kuhse J, Betz H, Sanes JR. Dual requirement for gephyrin in glycine receptor clustering and molybdoenzyme activity. Science, Nov. 13, 1998.

The National Institutes of Health, the Jane Coffin Childs Memorial Fund for Medical Research, the McKnight Foundation, the Deutsche Forschungsgemeinschaft and Fonds der Chemischen Industrie supported this research.

Washington University School of Medicine

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