ALS: A Vicious Cycle

A vicious cycle in which damage to nerve cells (neurons) in the spinal cord results in the loss of an important mechanism to protect neurons, causing more neuron loss, has been identified as a possible contributor to ALS (amyotrophic lateral sclerosis). Identification of this pathway opens the door to targeting it with therapeutic agents.

MDA-supported Yongjie Yang at Johns Hopkins University in Baltimore, with colleagues there and at other institutions, describe experiments in mice that clarify the relationship between loss of neurons and loss of clearance of glutamate, a potentially toxic chemical when present in excess, from the vicinity of the neurons.

The relationship between these phenomena was previously shown in laboratory studies involving cells but not animals.

Jeffrey Rothstein, director of the MDA/ALS Center at Johns Hopkins University in Baltimore, and an MDA research grantee, coordinated the investigators, and Yongjie Yang at Hopkins received direct MDA support for this project. The investigators published their findings March 26, 2009, in Neuron.

Normally, glutamate, a chemical transmitter of signals between nerve cells, is released by a sending neuron, docks on a receiving neuron, and is then quickly cleared away by glutamate transporter proteins produced by neighboring cells in the nervous system called astrocytes. Loss of one of these glutamate transporters, known as EAAT2, is believed to represent a common mechanism for disease propagation in both familial and nonfamilial ALS.

Yang and colleagues showed that, when glutamate docks (hits "receptors") on a receiving neuron, neighboring astrocytes start producing a protein called KBBP in mice, which in turn activates production of a glutamate transporter protein called GLT1 in mice and EAAT2 in humans. They say the KBBP protein in mice is identical to the human protein hnRNP K.

When the investigators analyzed the results of spinal cord injury, poisoning by the neurotoxin ricin, and an ALS-causing genetic mutation in the gene for the SOD1 protein, they saw a marked drop in both KBBP production and GLT1 production. They surmised that the damage sustained by the glutamate-transmitting neurons caused a reduction in glutamate signaling, which in turn caused a reduction in glutamate clearance.

They say their studies suggest an unfortunate "feed-forward" mechanism, in which loss of glutamate clearance may be the final blow in the demise of neurons from various types of insults, including ALS.

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