中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (12): 2505-2511.doi: 10.4103/1673-5374.313053

• 原著:退行性病与再生 • 上一篇    下一篇

P2X4受体参与调节帕金森病的自噬

  

  • 出版日期:2021-12-15 发布日期:2021-05-15
  • 基金资助:

    国家自然科学基金项目（81571225，81971192）

P2X4 receptor participates in autophagy regulation in Parkinson’s disease

Xue Zhang1, Jing Wang1, Jin-Zhao Gao1, Xiao-Na Zhang1, Kai-Xin Dou1, Wan-Da Shi1, An-Mu Xie1, 2, *   

  1. 1Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China; 2Neurological Regulation Institute of Qingdao University, Qingdao, Shandong Province, China
  • Online:2021-12-15 Published:2021-05-15
  • Contact: An-Mu Xie, xieanmu@163.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 81571225 and 81971192 (both to AMX).

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摘要：

功能失调的自噬可发生在神经退行性疾病，如帕金森病、亨廷顿病和阿尔茨海默病的过程中。P2X4受体是一种广泛表达于小胶质细胞和星形胶质细胞及中枢和周围神经系统的神经元中，参与调节细胞兴奋性、突触传递和神经炎症ATP调控的离子通道蛋白，但其在帕金森病中的作用尚不可知。（1）实验于中脑黑质致密部注射6-羟多巴胺建立帕金森病大鼠模型，于损伤前1周在相同部位注射P2X4-siRNA抑制P2X4受体的表达。见抑制P2X4受体表达，可减少阿扑吗啡诱导帕金森病模型大鼠的旋转，增加转杆实验的潜伏期，上调脑组织中酪氨酸羟化酶、脑源性神经营养因子、LC3-II/LC3I和Beclin-1的表达以及TrkB磷酸化水平，同时降低p62水平；（2）结果表明，P2X4受体激活可能通过调控脑源性神经营养因子/TrkB细胞内信号通路抑制神经元自噬，导致中脑黑质多巴胺能神经元损伤，而抑制P2X4受体激活自噬，提示P2X4受体可能是帕金森病治疗的潜在新靶点。实验于2016年4月12日经青岛大学附属医院动物实验伦理委员会批准（批准号QYFYWZLL26119）。

https://orcid.org/0000-0003-2591-467X (An-Mu Xie)

关键词: P2X4受体, 脑源性神经营养因子, TrkB, 自噬, 多巴胺能神经元, 神经元变性, 帕金森病, 6-羟多巴胺, 阿朴吗啡

Abstract: Dysfunctional autophagy often occurs during the development of neurodegenerative diseases, such as Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease. The purinergic P2X4 receptor is an ATP-gated ion channel that is widely expressed in the microglia, astrocytes, and neurons of the central and peripheral nervous systems. P2X4R is involved in the regulation of cellular excitability, synaptic transmission, and neuroinflammation. However, the role played by P2X4R in Parkinson’s disease remains poorly understood. Rat models of Parkinson’s disease were established by injecting 6-hydroxydopamine into the substantia nigra pars compacta. P2X4R-targeted small interfering RNA (siRNA) was injected into the same area 1 week before injury induction to inhibit the expression of the P2X4 receptor. The results showed that the inhibition of P2X4 receptor expression in Parkinson’s disease model rats reduced the rotation behavior induced by apomorphine treatment, increased the latency on the rotarod test, and upregulated the expression of tyrosine hydroxylase, brain-derived neurotrophic factor, LC3-II/LC3-I, Beclin-1, and phosphorylated tropomyosin receptor kinase B (TrkB) in brain tissue, while simultaneously reducing p62 levels. These findings suggest that P2X4 receptor activation might inhibit neuronal autophagy through the regulation of the brain-derived neurotrophic factor/TrkB signaling pathway, leading to dopaminergic neuron damage in the substantia nigra and the further inhibition of P2X4 receptor-mediated autophagy. These results indicate that P2X4 receptor might serve as a potential novel target for the treatment of Parkinson’s disease. This study was approved by the Animal Ethics Committee of Affiliated Hospital of Qingdao University (approval No. QYFYWZLL26119) on April 12, 2016.


Key words: 6-hydroxydopamine, apomorphine, brain-derived neurotrophic factor, dopaminergic neurons, neuron degeneration, P2X4R, Parkinson’s disease, TrkB, autophagy

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