Commentary ( Two Hits with One Shot - A Possibility of Simultaneous Targeting Motor Neuron Loss and Depression in ALS by Upregulating ADAR2 )

A leading hypothesis for the selective death of motor neurons in sporadic amyotrophic lateral sclerosis (ALS) is excitotoxicity mediated by Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors. The AMPA receptors are assembled from 4 subunits and their permeability for Ca2+ is determined by the absence of the glutamate receptor subunit type 2 (GluR2), associated with an increased portion of unedited GluR2 mRNA at the glutamine/arginine (Q/R) site. RNA editing at this location is predominantly catalyzed by adenosine deaminase acting on RNA 2 (ADAR2). Thus, the observation that a substantial portion of Q/R site unedited GluR2 mRNA is present in postmortem spinal cord tissue of sporadic ALS patients suggests inefficiency of ADAR2 to be a disease-specific molecular dysfunction in ALS. To decide whether this malfunction could be a cause of motor neuron death in vivo, Hideyama and colleagues developed a conditional ADAR2 knock-out mouse line (designated as AR2), which carries gene-targeted floxed ADAR2 alleles that become functionally ablated by Cre recombinase expressed from a transgene (VAChT-Cre.Fast) in approximately 50% of motor neurons. They demonstrated that only the ADAR2-lacking spinal motor neurons degenerated in these animals, and this could be prevented by generating Q/R site edited GluR2 in the absence of ADAR2 by a point mutation in the endogenous GluR2 alleles. These results convincingly demonstrate that the inefficient GluR2 Q/R site editing found in the spinal cords of patients with sporadic ALS proposes the decreased level of ADAR2 mRNA to be a direct cause of death of motor neurons in mice, which accentuates the detrimental role of elevated Ca2+ influx in motor neurons as a consequence of increased Ca2+-permeability of AMPA receptors.

From therapeutic point of view, an interesting aspect of the Ca2+-mediated cell death in ALS is connected with certain emotional reactions of the patients such as depression and anxiety, which has received particular attention in ALS. Although many researchers with experience with ALS challenge the lay opinion of an increased risk of developing major depressive disorder in ALS, studies using standardized methodology assessing nonphysical symptoms reported an occurrence exceeding the prevalence of that in the general population. There is growing evidence that besides the monoaminergic system the glutamatergic system, particularly N-methyl-D-aspartate receptor mediated Ca2+-entry plays an important role in the pathobiology of major depressive disorder. It is thus intriguing that conventional tricyclic antidepressants, specific serotonin reuptake inhibitors and serotonin/norepinephrine reuptake inhibitors not only down-regulate N-methyl-D-aspartate receptors but - at least in an in vitro model system - have the potency to enhance GluR2 Q/R site-editing either by up-regulating ADAR2 mRNA expression level, or through other unidentified mechanisms. It will now be important to determine whether these drugs exert a similar protective effect on motor neurons in in vivo models of ALS, and thus constitute a new therapeutic approach for this disease.