Ferreira Diana G, Batalha Vânia L, Vicente Miranda Hugo, Coelho Joana E, Gomes Rui, Gonçalves Francisco Q, Real Joana I, Rino José, Albino-Teixeira António, Cunha Rodrigo A, Outeiro Tiago F, Lopes Luísa V
Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa.
Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Germany.
Cereb Cortex. 2017 Jan 1;27(1):718-730. doi: 10.1093/cercor/bhv268.
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 exposure was 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.
聚集的α-突触核蛋白（aSyn）异常积累是散发性和家族性帕金森病（PD）及相关突触核蛋白病的一个标志。最近的研究表明腺苷A2A受体（A2AR）拮抗剂在帕金森病中具有神经保护作用。然而，这种神经保护作用的确切分子机制仍不清楚。我们评估了A2AR阻断或基因缺失（A2AR基因敲除，A2AR KO）对aSyn寡聚体诱导的突触可塑性和神经元细胞死亡的影响。我们发现，在A2AR基因敲除小鼠或A2AR阻断后，通过一种依赖NMDA受体的机制，与aSyn暴露相关的长时程增强（LTP）损伤得到了挽救。在过表达aSyn的SH-SY5Y细胞和暴露于aSyn的大鼠原代神经元培养物中评估了这些效应的潜在机制。在这两种情况下，细胞死亡都被选择性A2AR拮抗剂所阻止。有趣的是，这些受体的阻断并不干扰aSyn的寡聚化，反而降低了显示aSyn包涵体的细胞百分比。总之，我们的数据提出了一种可能性，即A2AR拮抗剂的良好记录效应涉及对aSyn聚集后期的控制，从而预防相关的神经毒性。这些发现表明A2AR是开发治疗帕金森病和相关突触核蛋白病有效药物的一个重要靶点。
