Role of neuroinflammation and latent transcription factors in pathogenesis of Parkinson's disease
Role of neuroinflammation and latent transcription factors in pathogenesis of Parkinson's disease
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DOI：
10.1080/01616412.2016.1249997
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发表时间：
2016-12-01
影响因子：
1.9
通讯作者：
Pant, Kamlesh Kumar
中科院分区：
文献类型：
--
作者：
Pal, Rishi;Tiwari, Prafulla Chandra;Pant, Kamlesh Kumar
帕金森病（PD）是第二种最常见的年龄相关的进行性神经退行性疾病，其特征在于多巴胺能神经元的损失、聚集蛋白质的细胞质内含物（路易体）和神经炎症。神经元的炎症引起各种炎症介质（IFN、EGF、IL 5、IL 6、HGF、LIF和BMP 2）的释放。神经炎症的标志是CNS实质中存在活化的小胶质细胞和反应性星形胶质细胞，以及细胞因子、趋化因子、肾上腺素、补体级联蛋白和活性氧和氮物质（ROS/RNS）的产生增加，这在某些情况下可导致血脑屏障破坏和适应性免疫系统的直接参与。潜伏性转录因子如NF-κ B、STAT 3、AP 1和SMAD 7、Toll样受体和FAF 1在活化的小胶质细胞中组成性上调。Toll样受体在被激活时促进NF-κ B信号传导，从而促进神经炎症的恶性循环。这些转录因子通过p53和其他死亡结构域受体将多巴胺能神经元带到凋亡途径。神经保护信号通路如mTOR、SOCS和TGF-β在PD发展过程中下调。总之，我们可以说，促进炎症的转录因子如NF-κ B、STAT 3、AP 1和Toll样受体在PD患者中组成性上调，而神经保护通路如mTOR、TGF-β和YY 1在PD患者的小胶质细胞中显著下调。
Parkinson's disease (PD) the second most common age-associated progressive neurodegenerative disorder is characterized by loss of dopaminergic neurons, cytoplasmic inclusions of aggregated proteins (Lewy bodies), and neuroinflammation. The inflammation of neurons causes release of various inflammatory mediators (IFNs, EGF, IL5, IL6, HGF, LIF and BMP2). The hallmarks of neuroinflammation are the presence of activated microglia and reactive astrocytes in the parenchyma of the CNS and increased production of cytokines, chemokines, prostaglandins, complement cascade proteins, and reactive oxygen and nitrogen species (ROS/RNS) which in some cases can result in disruption of the blood brain barrier and direct participation of the adaptive immune system. Latent transcription factors such as NF-kappa B, STAT 3, AP1, and SMAD 7, Toll like receptors and FAF 1 are constitutively upregulated in activated microglia. Toll-like receptors when activated promote NF-kappa B signaling thus promoting a vicious cycle of neuroinflammation. These transcription factors take dopaminergic neurons to apoptotic pathway via p53 and other death domain receptors. Neuroprotective signaling pathways such as mTOR, SOCS, and TGF-beta down regulated during development of PD. YY1 signaling, which has protective effect against alpha-Synuclein toxicity, is significantly decreased in PD patients.In summary we can say that transcription factors promoting inflammation such as NF-kappa B, STAT 3, AP 1, and Toll-like receptors are constitutively upregulated in PD, while neuroprotective pathways such as mTOR, TGF-beta, and YY1 are substantially downregulated in microglia of PD patients.