Novel etiological and therapeutic strategies for neurodiseases: RNA editing enzyme abnormality in sporadic amyotrophic lateral sclerosis

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. © 2010 the japanese pharmacological society.