To investigate the putative interaction between chronic exposure to adenosine receptor antagonist caffeine and genetic influences on Parkinson's disease (PD), we determined whether deletion of the adenosine A2A receptor in knockout (KO) mice protects against dopaminergic neuron degeneration induced by a mutant human α-synuclein (hm2SYN) transgene containing both A53T and A30P. The A2A KO completely prevented loss of dopamine and dopaminergic neurons caused by the mutant α-synuclein transgene without altering levels of its expression. The adenosine A2A receptor appears required for neurotoxicity in a mutant α-synuclein model of PD. Together with prior studies the present findings indirectly support the neuroprotective potential of caffeine and more specific A2A antagonists. Ann Neurol 2012;71:278–282