Such mitochondrial impairment is likely to be involved in the reduction of energy production that favours synaptic loss.49 Puzzlingly, previous data obtained in a model of Niemann-Pick disease indicated that activation of A2AR rescues compromised mitochondrial functionality (mitochondrial inner membrane potential and expression of complex IV of the mitochondrial respiratory chain) in line with other studies.50,51 Mechanisms linking this neuronal-autonomous effect of A2AR upregulation that negatively impacts mitochondrial function will therefore deserve further studies. The gene discussed is ADORA2A; the disease is Niemann-Pick disease.