Gene ID May Unlock New Door to Glutamate Control

A new way to reduce levels of the potentially toxic chemical glutamate in the nervous system may have been identified by MDA grantee David Featherstone and colleagues at the University of Illinois-Chicago.

In a paper published in the Jan. 3 issue of the Journal of Neuroscience, the investigators describe their identification of the gene for a protein they’ve called “genderblind,” whose job is to help regulate glutamate concentrations outside cells. Without genderblind, glutamate levels drop dramatically, a desirable effect in amyotrophic lateral sclerosis (ALS).

Excess glutamate around nerve cells has been implicated as a cause or at least an exacerbating factor in ALS, but attempts to reduce it have been only moderately successful.

Riluzole (Rilutek), the only medication specifically approved for ALS treatment by the U.S. Food and Drug Administration, reduces glutamate levels modestly, probably mainly by interfering with cellular release of the compound.

Ceftriaxone, now being tested in an ALS clinical trial, reportedly increases the transport of glutamate away from the area around nerve cells.

Genderblind (so named because a mutated form of it causes fruit flies to behave without regard to their gender) moves glutamate from inside glial cells (supportive cells in the nervous system) to the extracellular (outside cells) area. Blocking it -- at least in flies -- caused a dramatic fall in extracellular glutamate.

Featherstone says there’s a long road between a fruit fly study and human trials of genderblind blocking agents, if they could be developed for human use, but that it may be worth following.

“If some specific inhibitors were developed, it would certainly be worth trying them in mice and eventually in clinical studies,” he says, “as I suspect they might be far more effective at lowering extracellular glutamate than riluzole or drugs aimed at glutamate transporters. In short, I think genderblind-like proteins represent an exciting new class of drug target that could help treat ALS.”