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.

Full-text preview

Available from:
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Nov 2015 · Cerebral Cortex

  • No preview · Article · Oct 1976 · Human Biology
  • [Show abstract] [Hide abstract]
    ABSTRACT: The recent approval by the FDA of cancer vaccines and drugs that blockade immunological negative regulators has further enhanced interest in promising approaches of the immunotherapy of cancer. However, the disappointingly short life extension has also underscored the need to better understand the mechanisms that prevent tumor rejection and survival even after the blockade of immunological negative regulators. Here, we describe the implications of the "metabolism-based" immunosuppressive mechanism, where the local tissue hypoxia-driven accumulation of extracellular adenosine triggers suppression via A2 adenosine receptors on the surface of activated immune cells. This molecular pathway is of critical importance in mechanisms of immunosuppression in inflamed and cancerous tissue microenvironments. The protection of tumors by tumor-generated extracellular adenosine and A2 adenosine receptors could be the misguided application of the normal tissue-protecting mechanism that limits excessive collateral damage to vital organs during the anti-pathogen immune response. The overview of the current state of the art regarding the immunosuppressive effects of extracellular adenosine is followed by a historical perspective of studies focused on the elucidation of the physiological negative regulators that protect tissues of vital organs from excessive collateral damage, but, as a trade-off, may also weaken the anti-pathogen effector functions and negate the attempts of anti-tumor immune cells to destroy cancerous cells.
    No preview · Article · Jan 2013 · Journal of Molecular Medicine
Show more