A pivotal role of FOS-mediated BECN1/Beclin 1 upregulation in dopamine D2 and D3 receptor agonist-induced autophagy activation.
A pivotal role of FOS-mediated BECN1/Beclin 1 upregulation in dopamine D2 and D3 receptor agonist-induced autophagy activation.
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FOS 介导的 BECN1/Beclin 1 上调在多巴胺 D2 和 D3 受体激动剂诱导的自噬激活中发挥关键作用。
DOI：
10.1080/15548627.2015.1100930
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发表时间：
2015-11-02
期刊：
影响因子：
13.3
通讯作者：
Liu CF
中科院分区：
文献类型：
--
作者：
Wang JD;Cao YL;Li Q;Yang YP;Jin M;Chen D;Wang F;Wang GH;Qin ZH;Hu LF;Liu CF
自噬功能障碍与帕金森病（PD）的发病机制有关。BECN 1/Beclin 1是自噬和其他细胞过程的关键调节因子;然而，对BECN 1在PD中的功能和调节知之甚少。在这项研究中，我们报告了多巴胺D2和D3受体（DRD 2和DRD 3）激活普拉克索和喹吡罗可以增强BECN 1转录和促进自噬激活的几种细胞系，包括PC 12，MES 23. 5和分化的SH-SY 5 Y细胞，也在酪氨酸羟化酶阳性的原代中脑神经元。此外，我们在大鼠和人Becn 1/BECN 1启动子中鉴定了一个新的FOS（FBJ鼠骨肉瘤病毒癌基因同源物）结合序列（5′-TGCCTCA-3′），并揭示了FOS结合在多巴胺激动剂增强PC 12细胞Becn 1转录中的重要作用。此外，我们证明了细胞内Ca 2+升高的关键作用，随后是CAMK 4（钙/钙调蛋白依赖性蛋白激酶IV）和CREB（cAMP反应元件结合蛋白）的磷酸化增强，FOS表达和自噬活性增加。更重要的是，普拉克索处理通过促进自噬通量改善了鱼藤酮处理的PC 12细胞中SNCA/α-突触核蛋白的蓄积，该细胞过度表达野生型或A53 T突变SNCA。在SNCAA 53 T转基因小鼠的黑质和纹状体中也证明了这种作用。通过与DRD 2和DRD 3拮抗剂和Becn 1 siRNA共处理，可减弱普拉克索对SNCA蓄积的抑制作用。因此，我们的研究结果表明，DRD 2和DRD 3激动剂可能通过BECN 1依赖性途径诱导自噬激活，并有可能减少PD中SNCA的积累。
Autophagy dysfunction is implicated in the pathogenesis of Parkinson disease (PD). BECN1/Beclin 1 acts as a critical regulator of autophagy and other cellular processes; yet, little is known about the function and regulation of BECN1 in PD. In this study, we report that dopamine D2 and D3 receptor (DRD2 and DRD3) activation by pramipexole and quinpirole could enhance BECN1 transcription and promote autophagy activation in several cell lines, including PC12, MES23.5 and differentiated SH-SY5Y cells, and also in tyrosine hydroxylase positive primary midbrain neurons. Moreover, we identified a novel FOS (FBJ murine osteosarcoma viral oncogene homolog) binding sequence (5′-TGCCTCA-3′) in the rat and human Becn1/BECN1 promoter and uncovered an essential role of FOS binding in the enhancement of Becn1 transcription in PC12 cells in response to the dopamine agonist(s). In addition, we demonstrated a critical role of intracellular Ca2+ elevation, followed by the enhanced phosphorylation of CAMK4 (calcium/calmodulin-dependent protein kinase IV) and CREB (cAMP responsive element binding protein) in the increases of FOS expression and autophagy activity. More importantly, pramipexole treatment ameliorated the SNCA/α-synuclein accumulation in rotenone-treated PC12 cells that overexpress wild-type or A53T mutant SNCA by promoting autophagy flux. This effect was also demonstrated in the substantia nigra and the striatum of SNCAA53T transgenic mice. The inhibition of SNCA accumulation by pramipexole was attenuated by cotreatment with the DRD2 and DRD3 antagonists and Becn1 siRNAs. Thus, our findings suggest that DRD2 and DRD3 agonist(s) may induce autophagy activation via a BECN1-dependent pathway and have the potential to reduce SNCA accumulation in PD.