STUDIES SUPPORT ROLE OF GLUTAMATE, RNA PROCESSING
IN LOU GEHRIG’S DISEASE

TUCSON, Ariz., March 5, 2004 — The possibility that a central nervous system signaling chemical called glutamate has a role in the development or exacerbation of amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) has been strengthened by two recent studies, the Muscular Dystrophy Association announced today.

The findings suggest targets for future therapies in this paralyzing disease, which generally strikes adults in late middle age, and is usually fatal within five years.

“We’re really excited about these findings,” said Sharon Hesterlee, MDA’s research development director. “We’ve known about the involvement of glutamate in ALS for some time now, but here we have some new clues as to how this chemical may go wrong.”

MDA research grantee Jeffrey Rothstein of the Department of Neurology at Johns Hopkins University School of Medicine in Baltimore, where he also directs an MDA-supported ALS Center, was part of a research team that published findings online in Annals of Neurology, showing that people with ALS make a variant form of a protein whose usual role is to remove glutamate after it has carried a signal from one nerve cell to another.
This type of protein is called a glutamate transporter, and it’s vital for keeping glutamate from building up and poisoning cells.

The type of transporter made by the ALS patients may not be as good as the one normally produced, the researchers suggest, although they haven’t yet proven that.

They do know that the difference in the two transport proteins — EAAT2 and EAAT2b — comes about because of a change in the way RNA, the chemical that’s made from DNA and immediately precedes protein manufacturing, is assembled, a process known as “RNA splicing.”

And they also know that glutamate transport is known to be faulty in people with ALS whose tissues have been studied to detect this problem.

In a separate study, a Japanese research group found that samples of muscle-controlling nerve cells from ALS patients are different from those of people without ALS in another way — but one that also implicates both glutamate and RNA processing.

Shin Kwak of the Department of Neurology at the University of Tokyo found that 56 percent of the nerve cells examined from people with ALS contained abnormal glutamate receptors sites on the cell surface where glutamate normally docks. None of these abnormal receptors were found in cells taken from people who didn’t have ALS.

The kind of receptor that most people have keeps calcium out of the targeted cell, while the kind that was found in the ALS patients allows calcium to gain entry. Since excess calcium in the wrong place is a well-known cause of cell death, the calcium-permeable glutamate receptors could be a key factor in the disease.

The Japanese researchers, who published in the journal Nature, say that the nerve cells of ALS patients can’t perform a vital step in the final stages of RNA processing which makes the difference between a receptor that lets calcium through and one that doesn’t.

Rothstein, who has been studying glutamate transport for about a decade, said the Japanese finding describes “another hit in the glutamate pathway.” He says both findings help build the argument for the key role of glutamate signaling in ALS.

The only treatment approved by the U.S. Food and Drug Administration for ALS at this time is riluzole, a drug that partially blocks glutamate in the nervous system.

“You can manipulate the glutamate system,” Rothstein says. But he adds that researchers might now also be able to target the RNA processing errors uncovered by these two studies.

“There are RNA editing and splicing enzymes,” he says, offering these as possible areas for investigation. “Anything that gives you new targets is good.”

MDA is a voluntary health agency working to defeat ALS and more than 40 other neuromuscular diseases through programs of worldwide research, comprehensive services, and far-reaching professional and public health education.