Of all the weapons in the bioterrorist arsenal, none is as potent as botulinum neurotoxin, which causes botulism--a potentially fatal disease with symptoms that include severe paralysis of the limbs and respiratory muscles. Just 1 gram of botulinum neurotoxin, evenly dispersed and inhaled, could kill more than a million people, according to a 2001 study in the Journal of the American Medical Association. Botulinum also holds the distinction of being the only high-risk biological weapon that's approved for therapeutic and cosmetic use as the active ingredient in the widely prescribed commercial products Botox and Dysport.
Now, for the first time, scientists from Stanford University and the Medical School of Hannover in Germany have figured out how this powerful neurotoxin binds to and disables individual nerve cells. Researchers say their discovery, published in the Dec. 13 online edition of the journal Nature, could lead to new treatments for botulism, which also is caused by eating botulinum-contaminated food.
"Our results could provide the basis for the rational development of preventive vaccines against botulinum neurotoxins," said study co-author Axel T. Brunger, a Howard Hughes Medical Institute (HHMI) investigator who holds professorships in four Stanford units--the Molecular and Cellular Physiology Department, the Neurology and Neurological Sciences Department, the Stanford Synchrotron Radiation Laboratory (SSRL) and, by courtesy, the Structural Biology Department.
"Effective binding inhibitors or vaccines are urgently needed, given the concerns about the safety and scarcity of current botulism therapies," Brunger added.
Along with the Stanford experiment, Nature simultaneously published a separate study led by scientists from the Scripps Research Institute. In both studies, scientists used a technique called X-ray crystallography to produce the first three-dimensional, atomic-scale images of botulinum neurotoxin binding to its specific protein receptor on the surface of a neuron.
The scientists discovered that the neurotoxin works by taking advantage of the neuronal signaling system in which tiny protein-lipid sacs (synaptic vesicles) carry chemical messages (neurotransmitters) from inside the nerve cell to the surface where the neurotransmitters are released. The vesicles then are reprocessed inside the neuron and replenished with neurotransmitters.
The researchers found that botulinum disrupts this process by recognizing and binding to a specific protein receptor, called synaptotagmin, which is an important component of synaptic vesicles. "Botulinum neurotoxin basically hijacks synaptotagmin in order to get inside the neuron," Brunger explained. Once inside, the vesicle releases the neurotoxin, which has the devastating effect of blocking the release of acetylcholine, a neurotransmitter that signals the muscle to contract.
The Brunger team also was surprised to discover that the toxicity of botulinum can be dramatically reduced by altering just one amino acid in its molecular structure. This finding suggests the possibility of designing a specific inhibitor that will prevent the neurotoxin from binding to the neuron surface.
In addition to treating botulism, the scientists said that their new findings may lead to novel remedies for several neuromuscular conditions, including uncontrolled blinking (blepharospasm), lazy eye (strabismus), involuntary neck muscle contractions (cervical dystonia) and even symptoms of cerebral palsy. "Botulinum neurotoxins have become powerful therapeutic tools in the treatment of neurological, ophthalmic and other disorders caused by abnormal, excessive or inappropriate muscle contractions," Brunger said. "Experimental studies are also under way that explore their use in managing chronic pain, such as headaches and migraines. Our work also may lead the way to designing modified neurotoxins as a drug delivery system with altered targeting specificities."
The Stanford study was co-written by lead author Rongsheng Jin, an HHMI postdoctoral scholar in the Brunger Lab, and Andreas Rummel and Thomas Binz of the Medical School of Hannover. X-ray crystallography was conducted at SSRL and the Lawrence Berkeley National Laboratory. Research was supported by HHMI, the U.S. Department of Energy, the National Institutes of Health, the Department of Defense, the Defense Threat Reduction Agency and the German Research Foundation.
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