Glutamate

Overview

Prolonged excitation is toxic to nerve cells. Neurobiologists recognize that the nerve cell messenger, glutamate, can cause harm when its messages are overwhelming. Normally glutamate is swiftly cleared from the nerve cell junctions to keep the messages brief. Molecules called transporters aid in keeping glutamate in proper concentrations around nerve cells. Abundant evidence points to glutamate as a destructive factor in ALS and investigators are working to find out how this can be changed. Gene therapy approaches are under investigation to deliver glutamate transporters to cells affected by ALS. Other avenues towards control of glutamate in ALS are also under active investigation.

What is Glutamate?

Nerve cells pass signals to each other and to their target organs by releasing messenger molecules, called transmitters. Many are simple amino acids such as the one called glutamate.
The message is intended to tell the recipient neuron whether to fire off its own neurotransmitters. As with all neurotransmitters, glutamate docks at specific recognition molecules on the receiving neuron. Glutamate is then swiftly cleared from the nerve cell junctions to keep the message brief. Prolonged excitation is toxic to nerve cells, and neurobiologists recognize that glutamate can cause harm when the messages are overwhelming, as in stroke or epilepsy.

A diseased neuron. NIH

Glutamate's toxicity is apparently due to calcium flooding the cell. Calcium is supposed to briefly enter the neuron with each signal and triggers the cell to fire off its own signals and adjust its own activities accordingly. But prolonged calcium inside the cell evidently can do damage, and will even activate programmed cell death (see section on apoptosis).

Research in the early 1990s determined that ALS patients have raised levels of glutamate in the fluid bathing the brain and spinal cord. In fact, 40 percent of sporadic cases of ALS are characterized by this elevated glutamate in cerebrospinal fluid (CSF). Abundant evidence points to glutamate as a destructive factor in ALS. The first and so far only approved specific treatment for ALS is riluzole, a drug that modulates glutamate.

The transporter that clears glutamate is called EAAT2 (an "excitatory amino acid transporter;" as glutamate is one of the amino acids that serve as transmitters). In ALS, transport of glutamate is slowed into the glial cells that surround the junctions of motor neurons. Indeed, a mutation has been identified in an ALS patient that prevented the transporter from working properly.

Researchers are working towards gene therapy approaches to deliver the glutamate transporter molecule to cells affected by ALS. Other avenues towards control of glutamate in ALS are also under active investigation.