Researchers examine alternative role for proteins

Dr. Jekyll and Mr. Hyde, meet Dr. James McNamara and Zhi-Qi Xiong.

McNamara and Xiong, two Duke neurobiologists, believe they have discovered a set of proteins that, similar to the fictitious character of Robert Louis Stevenson's novel, usually function to rid the body of foreign invaders, but that under certain circumstances can attack the body's immune system.

According to their recent research, patients who have autoimmune diseases such as lupus or rheumatoid arthritis and who then experience minor injuries--such as seizures, fainting, trauma or minor strokes--can have their neurons attacked by the proteins, called complement proteins. Each of the attacks causes the release of the neurotransmitter glutamate, which McNamara and Xiong believe sensitizes the neurons to further attacks.

The researchers' findings could lead to drugs capable of mitigating the pain of autoimmune diseases, as well as diseases such as Alzheimer's and multiple sclerosis, whose conditions significantly worsen following a minor injury.

But John Lynch, associate professor of neurology, noted that McNamara's research may be limited to Rasmussen's disease.

"It's a very specific trigger for a very specific disease," he said. "If you can understand that mechanism, it will be a great tool, but it's not something that can definitely be generalized."

McNamara and Xiong's discoveries came about while they were studying Rasmussen's Encephalitis--a rare, partly autoimmune disease in which children suffer from severe epileptic seizures, causing damage to only one half of the brain. While studying the brains of children with the disease, they found they were always able to identify the neurons in the membrane attack complex--the terminal site for complement proteins--and that the neurons were being killed off by the proteins.

This led them to believe that the complement proteins were destroying the neurons. Oddly enough, when they placed the complement proteins in a culture with neurons, the neurons appeared to be resistant.

"This didn't make sense," McNamara said. "Why were they getting attacked in the brain, yet in tissue culture, appeared to be resistant?"

McNamara and Xiong realized, then, that the one difference between the cells in the children's brain and the cells in the culture was that the ones in the culture did not have seizures.

"We then gave them seizures by pulsing them briefly with an excitatory substance," McNamara said. The excitatory substance, glutamate, then transformed the neurons from being resistant to complement, to sensitive. The neurons were, in turn, destroyed.

"The neurons try to fend off complement since neurons have their own defenses. If you pulse them with glutamate, though, you disarm them and the complement wins," McNamara said, describing this "battle for survival."

Normally, glutamate functions as a communication method across the synapses of neurons of the brain. However, now it appears to sensitize the neurons to attacks of complement proteins.

In the future, McNamara and Xiong hope to understand better the molecular mechanisms by which the glutamate sensitizes neurons to complement proteins, so that a preventative drug can be designed.

McNamara also said that their research could help lead to drugs for Alzheimer's, rheumatoid arthritis and sufferers of other common diseases, which would then inhibit the complement proteins before they reach the membrane attack complex and destroy the neurons.

Their research opens up a lot of doors for sufferers of neurodegenerative diseases.

"This could save humans a lot of misery," McNamara said.


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