We then further investigated the role of A1R in ALS using the same approach and the same disease model (Nascimento et al., 2015) and found that the A1R/A2AR functional cross-talk is lost in the pre-symptomatic phase, so that the ability of A1R to brake the action of A2AR is lost, which might explain the exacerbation of the A2AR signaling at this disease state. Here, ADORA2A is linked to amyotrophic lateral sclerosis.