Causes of ALS: Excitotoxicity

One of the most-studied mechanisms for motor neuron death involves their abnormal stimulation by the amino acid glutamate. 

Normally, glutamate acts as a neurotransmitter, carrying messages across synapses throughout the brain and spinal cord. The presence of too much glutamate, however – this occurs if neurons are overstimulated or cell chemistry goes awry – kills neurons. Normally, this buildup is prevented by glutamate transporters, molecules embedded in cell membranes that act like “sponges” to clear the neurotransmitter out of harm’s way. Glutamate transporters are most plentiful at nerve cells’ membranes located at synapses. Even more exist on the cell membranes of astrocytes, neurons’ central nervous system companion cells.

In the early 1990s, Packard investigators were the first to suggest that cells of ALS patients and animal models had major defects in glutamate neurotransmission. A large study of nearly 400 patients with sporadic ALS showed some 40 percent had increased glutamate levels in cerebrospinal fluid – a byproduct of excitotoxicity. The higher the levels, the more severe the disease.

Center scientists and others proved glutamate-based excitotoxicity is part of ALS, part of a process leading to motor neurons’ death. A key defect here likely centers on the glutamate transporters. They’re either inefficient or don’t exist in sufficient supply to prevent glutamate buildup. Up to 80 percent of ALS patients have some abnormality in glutamate transporters, our studies show.

ALS model mice have less than half of the normal glutamate transporters in their spinal cords, with the die-back beginning well before symptoms start. Remove glutamate transporters from ALS mice entirely and neurons die swiftly.

Earlier Packard research showed that overexpression of glutamate transporters in mouse models delays onset of symptoms and extends life. More recent Center-assisted studies showed that beta-lactam antibiotics – they boost transporter numbers – also delays disease onset, slows its progression and prolongs life.

The case for excitotoxicity's being a key process in ALS is a strong one. Packard research has helped shift the search for a cause of the disease solely on motor neurons. Evidence is also strong that other nervous system cells such as astrocytes can play a major part.

Excitotoxicity also makes a good therapeutic target and clinical studies are ongoing.

Learn more about the research projects funded and coordinated by the Packard Center for ALS Research at Johns Hopkins, and targeted at finding the causes of ALS and a cure. Subscribe to ALS Alert to stay informed about ALS research and clinical trials.