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Sporadic ALS: blame it on the editor

The sporadic form of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig disease, accounts for approximately 95% of all cases. Although mice with mutations in the gene encoding superoxide dismutase-1 (SOD-1) are used to study hereditary ALS, there is no universally accepted model for sporadic ALS. Circumstantial evidence, however, has pointed to glutamate, the major excitatory transmitter of the brain, as a culprit in sporadic cases of ALS1,2. Excessive activation of glutamate receptors initiates excessive calcium influx, activation of cell death pathways and production of free radicals.

Credit: Renee Lucas

This excitotoxic hypothesis now has a molecular underpinning in individuals with ALS. In a recent issue of Nature, Kawahara et al.3 provide evidence that abnormal post-transcriptional modification of mRNA encoding a glutamate receptor subunit may promote sporadic ALS. This abnormal RNA editing may lead to the exaggerated glutamate receptor activity and calcium influx that promotes excitotoxicity.

During RNA editing, gene-specified codons are altered by RNA-dependent deaminases (such as adenosine deaminase). In the case of the GluR2 glutamate receptor subunit, a crucial glutamine to arginine conversion in the putative second membrane domain affects the properties of the ion channel associated with the AMPA-type glutamate receptor4; among the effects are a drastic reduction in the permeability of this channel to calcium. In the absence of RNA editing, AMPA channels with GluR2 subunits are much more permeable to calcium.

The authors observed abnormal editing of GluR2 in spinal motoneurons from five individuals with ALS. But they saw no abnormal editing in any of the control postmortem specimens, including those with normal nervous systems and those with other neurologic disorders. Because of this abnormal editing, large calcium influxes can occur through AMPA-type glutamate receptors in these motoneurons, rendering them susceptible to cell death. This deficiency in RNA editing could potentially contribute to or even explain many cases of sporadic ALS.

The findings also point the way to mouse models of sporadic disease. An existing transgenic mouse with calcium-permeable GluR2 subunits develops a motoneuron disease late in life5. This mouse may be a reasonable model with which to study potential therapeutic drug responses in sporadic ALS. In the future, expressing unedited GluR2 subunits specifically in spinal motoneurons might generate an even better animal model.

One caveat of the study is that Kawahara et al. found that only spinal motoneurons were affected by aberrant RNA editing, and not upper motoneurons in the cerebral cortex; yet ALS affects both populations of neurons. Abnormal RNA editing, therefore, cannot explain all motoneuron loss in ALS. This caveat also raises the possibility that we are looking at the effect rather than the cause. Could another cause of the disease, such as oxidative or nitrosative stress, result in abnormal RNA editing and thus contribute to the demise of spinal motoneurons? Another question is whether other normally edited RNAs are also affected in sporadic cases of ALS, such as the GluR6 subunit of kainite-type glutamate receptors.

Whatever the mechanism, the new work raises the hope that studying dysfunction of RNA-editing enzymes may produce a new therapeutic target for sporadic ALS. Counteracting overly active, calcium-permeable glutamate receptors may also offer a new form of therapeutic intervention for the disease.


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Lipton, S. Sporadic ALS: blame it on the editor. Nat Med 10, 347 (2004).

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