遗传消融和过表达MAOB揭示了星形胶质细胞MAOB在帕金森病中的病理作用。,Experimental Neurobiology

当前位置： X-MOL 学术 › Exp. Neurobiol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

遗传消融和过表达MAOB揭示了星形胶质细胞MAOB在帕金森病中的病理作用。
Experimental Neurobiology ( IF 1.8 ) Pub Date : 2021-5-12 , DOI: 10.5607/en21007
Heeyoung An _{1,

2} , Jun Young Heo ₃ , C. Justin Lee _{1,

2} , Min-Ho Nam ₄

Affiliation

传统上认为帕金森氏病的病因是黑质致密部（SNpc）中的多巴胺能神经元死亡。这种传统观点最近受到以下提议的挑战：反应性星形胶质细胞通过过量释放GABA成为帕金森氏病病理学的关键角色。这种异常的星形细胞GABA是通过单胺氧化酶B（MAOB）的酶促作用合成的，据报道，其单药的抑制作用和基因沉默作用可显着减轻帕金森氏病动物模型中的帕金森氏症运动症状。但是，遗传消融和过表达的MAOB是否可以双向调节帕金森氏运动症状尚未得到验证。在这里，我们证明了MAOB的遗传消融阻止了MPTP诱导的星形胶质细胞GABA介导的相邻多巴胺能神经元以及帕金森氏运动症状的强直抑制的增强，这表明MAOB对于帕金森氏运动症状的必要性。此外，我们证明了GFAP-MAOB转基因小鼠，其中MAOB在星形胶质细胞特异性过表达的GFAP启动子下过表达，与野生型小鼠相比，其MPTP诱导的强直性抑制作用和帕金森氏运动症状加剧。星形细胞MAOB对帕金森氏运动症状的重要性。我们的研究为星形细胞MAOB依赖的补品GABA合成与帕金森氏运动症状的病理作用之间的因果关系提供了遗传证据。

"点击查看英文标题和摘要"

The Pathological Role of Astrocytic MAOB in Parkinsonism Revealed by Genetic Ablation and Over-expression of MAOB.

The cause of Parkinson's disease has been traditionally believed to be the dopaminergic neuronal death in the substantia nigra pars compacta (SNpc). This traditional view has been recently challenged by the proposal that reactive astrocytes serve as key players in the pathology of Parkinson's disease through excessive GABA release. This aberrant astrocytic GABA is synthesized by the enzymatic action of monoamine oxidase B (MAOB), whose pharmacological inhibition and gene-silencing are reported to significantly alleviate parkinsonian motor symptoms in animal models of Parkinson's disease. However, whether genetic ablation and over-expression of MAOB can bidirectionally regulate parkinsonian motor symptoms has not been tested. Here we demonstrate that genetic ablation of MAOB blocks the MPTP-induced augmentation of astrocytic GABA-mediated tonic inhibition of neighboring dopaminergic neurons as well as parkinsonian motor symptoms, indicating the necessity of MAOB for parkinsonian motor symptoms. Furthermore, we demonstrate that GFAP-MAOB transgenic mice, in which MAOB is over-expressed under the GFAP promoter for astrocyte-specific over-expression, display exacerbated MPTP-induced tonic inhibition and parkinsonian motor symptoms compared to wild-type mice, indicating the importance of astrocytic MAOB for parkinsonian motor symptoms. Our study provides genetic pieces of evidence for the causal link between the pathological role of astrocytic MAOB-dependent tonic GABA synthesis and parkinsonian motor symptoms.

更新日期：2021-05-13

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南