Novel Etiological and Therapeutic Strategies for Neurodiseases: RNA Editing Enzyme Abnormality in Sporadic Amyotrophic Lateral Sclerosis

Abstract

The motor neurons of patients with sporadic amyotrophic lateral sclerosis (ALS) express abundant Q/R site–unedited GluR2 mRNA, whereas those of patients with other motor neuron diseases including familial ALS associated with mutated SOD1 (ALS1) and those of normal subjects express only Q/R site–edited GluR2 mRNA. Because adenosine deaminase acting on RNA type 2 (ADAR2) specifically catalyzes GluR2 Q/R site–editing, it is likely that ADAR2 activity is not sufficient to edit this site completely in motor neurons of patients with sporadic ALS. Because these molecular abnormalities occur in disease- and motor neuron–specific fashion and induce fatal epilepsy in mice, we have hypothesized that GluR2 Q/R site–underediting due to ADAR2 underactivity is a cause of neuronal death in sporadic ALS. We found that cytoplasmic fragile X mental retardation protein interacting protein 2 (CYFIP2) mRNA had an ADAR2-mediated editing position using RNA interference knockdown. Our review will include a discussion of new ADAR2 substrates that may be useful for research on sporadic ALS. Keywords:: RNA editing, amyotrophic lateral sclerosis (ALS), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor, GluR2 Q/R, cytoplasmic fragile X mental retardation protein interacting protein 2 (CYFIP2), neurodisease