Molecular mechanism underlying death of motor neurons in model mice of amyotrophic lateral sclerosis

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Inefficient RNA editing of GluR2, a subunit of the L-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, at the Q/R site is a disease-specific and site-selective molecular abnormality in spinal motor neurons of ALS patients. Adenosine for the Q/R site of GluR2 pre-mRNA is converted to inosine (A-to-I conversion) by the enzyme called adenosine deaminase acting on RNA 2 (ADAR2) and failure to edit this site upregulates the Ca2+-permeable AMPA receptors containing Q/R site-unedited GluR2. To mimic the ALS pathogenesis, we generated genetically modified mice (designated as AR2) in which the ADAR2 gene was conditionally targeted in about a half of motor neurons using the Cre/loxP system. These AR2 mice showed a decline in motor function commensurate with the slow death of ADAR2-deficient motor neurons in the spinal cord and cranial motor nerve nuclei. Notably, neurons in nuclei of oculomotor nerves, which often escape degeneration in ALS, were not decreased in number despite of a significant decrease in GluR2 Q/R site-editing. All cellular and phenotypic changes in AR2 mice were prevented when the mice carried endogenous GluR2 alleles engineered to express edited GluR2 without ADAR2 activity. Thus, ADAR2 specifically edits the GluR2 Q/R site and loss of ADAR2 activity causes death of motor neurons by failure to edit the GluR2 Q/R site but not other ADAR2-mediated editing positions. Because of the similarity to the ALS pathogenesis, AR2 mice provides a tool for ALS research and therapy.