The role of AMPA receptor-mediated excitotoxicity in ALS: Is deficient RNA editing to blame?

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons. To date, glutamate modulator riluzole is the only drug that has proved effective against disease progression. Based on this evidence, it has been proposed that glutamate excitotoxicity contributes to the neurodegeneration observed in ALS, with α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) emerging as a likely candidate for glutamate receptor-mediated excitotoxicity. The calcium (Ca2+) conductance of AMPARs is determined by the presence of the edited GluR2 subunit, which renders the AMPAR Ca2+ impermeable. Of particular significance, reduced GluR2 editing at the Q/R site of AMPARs has been reported in spinal motor neurons of sporadic ALS patients. This review will examine the role of AMPAR-mediated excitotoxicity as a plausible mechanism to explain in part the selective motor neuron death observed in the pathogenesis of sporadic ALS.