02 Mar 2004

DNA makes RNA makes protein. That's how the dogma goes. But it doesn't always work out that way. In a minority of cases the DNA code is actually rewritten through RNA editing. In the February 26 Nature, Shin Kwak and colleagues at the University of Tokyo, Japan, report that failure of the RNA editor is linked to amyotrophic lateral sclerosis (ALS).

In mammals, one such edited transcript codes for the GluR2 subunit of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate) variety of glutamate receptor. In neurons, the GluR2 mRNA is edited so that in the GluR2 protein, a glutamine residue is switched to an arginine. In the mid-1990s, this editing step was shown to be essential for survival of mice.

First author Yukio Kawahara and colleagues wondered if failure of this editing process might lead to the motor neuron degeneration seen in ALS. To test this hypothesis, they isolated single motor neurons postmortem from volunteer patients and normal individuals, and examined the restriction enzyme digestion pattern of a GluR2 cDNA.

The restriction enzyme BbvI recognizes DNA amplified from edited RNA and cleaves it twice, leaving three fragments. But in DNA amplified from unedited RNA, there is only one restriction enzyme site, resulting in one cut and two fragments. When Kawahara tested the DNA amplified from neurons of control patients (five patients, for a total of 76 neurons tested), the RNA editing efficiency, as judged by the digestibility of amplified DNA, was 100 percent. In contrast, when she tested RNA editing efficiency in neurons isolated from ALS patients, she found it varied between zero and 100 percent for all five volunteers. On average, the efficiency in ALS motor neurons ranged from a low of about 40 percent (averaged from 11 neurons) for one patient, to a high of about 70 percent. In contrast, analysis of Purkinje cells from either ALS patients or controls showed that the RNA is always edited correctly.

The results suggest that failure to fully edit the GluR2 RNA may contribute to the demise of motor neurons. ALS, the authors claim, "may turn out to be a disease of RNA processing."—Tom Fagan