Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists solve the mystery of how Botox attacks nerves and eliminates wrinkles

13.12.2004


Every year, millions of people try to look younger by taking injections of Botox, a prescription drug that gets rid of facial wrinkles by temporarily paralyzing muscles in the forehead. Although best known as a cosmetic procedure, Botox injections also have been approved by the Food and Drug Administration (FDA) to treat uncontrolled blinking (blepharospasm), lazy eye (strabismus), involuntary muscle contractions in the neck (cervical dystonia) and acute underarm sweating (severe primary axillary hyperhidrosis).



Botox users might be surprised to learn that they’re actually receiving minute injections of a bacterial neurotoxin called botulinum, one of the most poisonous substances known. Exposure to large amounts of botulinum bacteria can cause a paralytic, sometimes-fatal disease called botulism. Last month, several Floridians were hospitalized with botulism after receiving injections of an anti-wrinkle treatment that authorities suspect was a cheap, non-FDA-approved imitation of Botox.

The botulinum toxin works by invading nerve cells, where it releases an enzyme that prevents muscle contraction. In recent years, scientists have determined that the enzyme binds to specific sites on proteins called SNAREs, which form a complex in the synapse between nerve and muscle cells. Without SNAREs, nerves cannot release the chemical signals that tell muscle cells to contract, and paralysis results. "The botulinum enzyme selectively attacks one of the SNARE proteins and cuts it into two pieces," said Stanford University Professor Axel T. Brunger. "That’s sufficient to disrupt its function. But the means by which the enzyme identifies and cleaves its target SNARE has been a subject of much speculation."


Now, Brunger and Stanford graduate student Mark A. Breidenbach have solved part of the puzzle. Their results, which will be published in the Dec. 12 online edition of the journal Nature, could help researchers develop alternative treatments for botulism and perhaps find new medical applications for Botox and other neurotoxins.

Clever machinery

There are seven forms of botulinum neurotoxin produced by seven different strains of the Clostridium botulinum bacterium, explained Brunger, a Howard Hughes Medical Institute investigator who holds professorships in three Stanford departments-molecular and cellular physiology, neurology and neurological sciences, and the Stanford Synchrotron Radiation Laboratory (SSRL). "The seven botulinum neurotoxins cut SNARE proteins at different sites along the surface," he said. "Why that is, we really don’t know exactly."

For the Nature study, the researchers focused on one of the seven forms, botulinum serotype A, which is the active ingredient in Botox. Breidenbach, lead author of the study, spent months in Brunger’s lab trying to crystallize a SNARE/botulinum A complex for laboratory analysis. Unfortunately, the botulinum A samples usually ended up slicing the SNARE target in two, rendering it useless. "The trick that Mark found was to introduce two specific mutations in the botulinum enzyme that would inhibit its function, but not to the degree that it would affect its structure," Brunger said. "These two mutations prevented it from cutting, so we could observe how it interacted with an intact SNARE."

The SNARE/botulinum A crystals were then taken to SSRL and the Lawrence Berkeley National Laboratories, where their structures were determined using a technique called x-ray crystallography. The results, published in Nature, reveal a complicated, three-dimensional maze of twisted proteins that look like gift-wrapping ribbons gone awry. "What we’ve shown is that part of the targeted SNARE protein literally wraps itself around the botulinum A enzyme, using a large portion of the enzyme’s surface for specific interactions," Brunger noted. "That’s the novel finding in our study."

It turned out that the SNARE protein was actually bound to more than two-dozen sites on the enzyme. "Such an extensive interface between a neurotoxin and its target is unheard of," Brunger said. "What botulinum A has accomplished with this large interaction area is a high degree of specificity with just a single unit. Often in biology such specificity is accomplished by having large complexes of auxiliary proteins working together, but these bacteria use a very simple mechanism-in this case, a single protein. It’s an extremely clever machinery."

New applications

Brunger hopes to determine the structures of other botulinum enzymes, along with a closely related neurotoxin that causes tetanus, another serious muscular disorder that affects hundreds of thousands of people worldwide every year. "Perhaps one could develop drugs that would treat botulism and tetanus by competing with specific binding sites on the surface of the neurotoxin,’’ he said. ’’The idea is that you could inject people with a compound that would have an immediate effect."

Further research also could open the door to novel medical applications, Brunger added. For example, recent experiments have shown that Botox may be useful for treating ringing in the ears (tinnitus), urinary incontinence and excess scarring that occurs when a wound heals. "This whole field is very young and evolving, and the picture we have so far is incomplete," he concluded.

Mark Shwartz | EurekAlert!
Further information:
http://www.stanford.edu

More articles from Life Sciences:

nachricht Ambush in a petri dish
24.11.2017 | Friedrich-Schiller-Universität Jena

nachricht Meadows beat out shrubs when it comes to storing carbon
23.11.2017 | Norwegian University of Science and Technology

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: New proton record: Researchers measure magnetic moment with greatest possible precision

High-precision measurement of the g-factor eleven times more precise than before / Results indicate a strong similarity between protons and antiprotons

The magnetic moment of an individual proton is inconceivably small, but can still be quantified. The basis for undertaking this measurement was laid over ten...

Im Focus: Frictional Heat Powers Hydrothermal Activity on Enceladus

Computer simulation shows how the icy moon heats water in a porous rock core

Heat from the friction of rocks caused by tidal forces could be the “engine” for the hydrothermal activity on Saturn's moon Enceladus. This presupposes that...

Im Focus: Nanoparticles help with malaria diagnosis – new rapid test in development

The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.

Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

IceCube experiment finds Earth can block high-energy particles from nuclear reactions

24.11.2017 | Physics and Astronomy

A 'half-hearted' solution to one-sided heart failure

24.11.2017 | Health and Medicine

Heidelberg Researchers Study Unique Underwater Stalactites

24.11.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>