Excitotoxic and oxidative cross-talk between motor neurons and glia in ALS pathogenesis

Excitotoxicity, resulting from deficiencies in astrocytic glutamate uptake, appears to play a crucial role in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, factors underlying the highly selective pattern of motor neuron loss that is the hallmark of the disease, and those underlying the loss of astrocytic glutamate transport, remain unresolved. Recent studies have provided insights into both of these questions. Evidence suggests that damaging reactive oxygen species, which appear to be preferentially produced in motor neurons in response to excitotoxic activation, could exit the motor neurons and induce oxidative disruption of glutamate transport in surrounding astrocytes. This would exacerbate excitotoxic stress to motor neurons, resulting in a vicious cycle that could underlie disease progression. These observations provide a new understanding of ALS pathogenesis that integrates diverse clues into a unified model that is broadly applicable to different forms of the disease.