Adenosine A2A receptor gene disruption protects in an a-synuclein model of Parkinson's disease

Harvard University, Cambridge, Massachusetts, United States
Annals of Neurology (Impact Factor: 9.98). 02/2012; 71(2):278-82. DOI: 10.1002/ana.22630
Source: PubMed


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 A(2A) receptor in knockout (KO) mice protects against dopaminergic neuron degeneration induced by a mutant human α-synuclein (hm(2)-αSYN) transgene containing both A53T and A30P. The A(2A) KO completely prevented loss of dopamine and dopaminergic neurons caused by the mutant α-synuclein transgene without altering levels of its expression. The adenosine A(2A) 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 A(2A) antagonists.

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    • "In addition, epidemiological studies show an inverse correlation between the consumption of caffeine, an A 2A R antagonist, and the risk of developing PD (Ascherio et al. 2001). Furthermore, A 2A R deregulation was suggested to play an important role in α-synuclein-mediated neurotoxicity, since α-synuclein-induced damage to striatal neurons was clearly reduced in A 2A R KO mice (Kachroo and Schwarzschild 2012). However, the extent to which A 2A R are involved in α-synucleinassociated toxicity, the underlying protective molecular mechanisms , or the impact on other brain areas is still unknown. "
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    ABSTRACT: Abnormal accumulation of aggregated α-synuclein (aSyn) is a hallmark of sporadic and familial Parkinson’s disease (PD) and related synucleinopathies. Recent studies suggest a neuroprotective role of adenosine A2A receptor (A2AR) antagonists in PD. Nevertheless, the precise molecular mechanisms underlying this neuroprotection remain unclear. We assessed the impact of A2AR blockade or genetic deletion (A2AR KO) on synaptic plasticity and neuronal cell death induced by aSyn oligomers.We found that impairment of LTP associated with aSyn exposurewas rescued in A2AR KO mice or upon A2AR blockade, through an NMDA receptor-dependent mechanism. The mechanisms underlying these effects were evaluated in SH-SY5Y cells overexpressing aSyn and rat primary neuronal cultures exposed to aSyn. Cell death in both conditions was prevented by selective A2AR antagonists. Interestingly, blockade of these receptors did not interfere with aSyn oligomerization but, instead, reduced the percentage of cells displaying aSyn inclusions. Altogether, our data raise the possibility that the well-documented effects of A2AR antagonists involve the control of the latter stages of aSyn aggregation, thereby preventing the associated neurotoxicity. These findings suggest that A2AR represent an important target for the development of effective drugs for the treatment of PD and related synucleinopathies.
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