1 Department of Anatomy and Neurobiology, College of Medicine, Kyung Hee University , Seoul, Republic of Korea.
2 Department of Biomedical Science, Graduate School, Kyung Hee University , Seoul, Republic of Korea.
OMICS. 2018 Jul;22(7):493-501. doi: 10.1089/omi.2018.0047.
While progressive dopaminergic neurodegeneration is responsible for the cardinal motor defects in Parkinson's disease (PD), new diagnostics and therapeutic targets are necessary to effectively address this major global health burden. We evaluated whether the adhesion G protein-coupled receptor B1 (ADGRB1, formerly BAI1, brain-specific angiogenesis inhibitor 1) might contribute to dopaminergic neuronal loss. We used bioinformatic analyses, as well as in vitro and in vivo PD models. We report in this study that ADGRB1 is decreased in PD and that the ADGRB1 level is specifically decreased in dopaminergic neurons in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. In primary mouse mesencephalic neurons and human neuroblastoma cell lines, 1-methyl-4-phenylpyridinium (MPP), a toxic metabolite of MPTP, suppressed the expression of ADGRB1. Moreover, we applied a network generation tool, Ingenuity Pathway Analysis, with the transcriptomics dataset to extend the upstream regulatory pathway of ADGRB1 expression. AMP-activated protein kinase (AMPK) was predicted as a regulator, and consequently, 5-aminoimidazole-4-carboxamide ribonucleotide, a specific activator of AMPK, reduced the ADGRB1 protein level. Finally, ADGRB1 overexpression decreased nuclear condensation induced by MPP treatment. Taken together, we observed that decreased ADGRB1 by activation of AMPK induced neuronal cell death in MPTP/MPP-mediated PD models, suggesting that ADGRB1 might potentially play a survival role in the neurodegenerative pathway of PD. These data offer new insights into dopaminergic cell death with therapeutic implications for neurodegenerative disorders.
虽然进行性多巴胺能神经退行性变是导致帕金森病 (PD) 主要运动缺陷的原因，但仍需要新的诊断和治疗靶点来有效应对这一主要的全球健康负担。我们评估了黏附 G 蛋白偶联受体 B1（ADGRB1，以前称为 BAI1，脑特异性血管生成抑制剂 1）是否可能导致多巴胺能神经元丢失。我们使用了生物信息学分析以及体外和体内 PD 模型。在本研究中，我们报告 ADGRB1 在 PD 中减少，并且 ADGRB1 水平在 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）中毒的小鼠黑质中的多巴胺能神经元中特异性降低。在原代小鼠中脑神经元和人神经母细胞瘤细胞系中，MPTP 的毒性代谢物 1-甲基-4-苯基吡啶（MPP）抑制了 ADGRB1 的表达。此外，我们应用了一种网络生成工具，即Ingenuity Pathway Analysis，该工具使用转录组数据集扩展了 ADGRB1 表达的上游调控途径。腺苷酸活化蛋白激酶（AMPK）被预测为一种调节剂，因此，5-氨基咪唑-4-甲酰胺核苷酸，一种 AMPK 的特异性激活剂，降低了 ADGRB1 蛋白水平。最后，ADGRB1 过表达减少了 MPP 处理诱导的核浓缩。总之，我们观察到 AMPK 激活导致 ADGRB1 减少，从而诱导 MPTP/MPP 介导的 PD 模型中的神经元细胞死亡，这表明 ADGRB1 可能在 PD 的神经退行性途径中发挥生存作用。这些数据为 AMPK 激活导致的多巴胺能神经元死亡提供了新的见解，并为神经退行性疾病的治疗提供了新的思路。
