An Heeyoung, Heo Jun Young, Lee C Justin, Nam Min-Ho
KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Korea.
Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon 34126, Korea.
Exp Neurobiol. 2021 Apr 30;30(2):113-119. doi: 10.5607/en21007.
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.
传统观点认为，帕金森病的病因是黑质致密部（SNpc）中多巴胺能神经元死亡。最近，这一传统观点受到了挑战，有观点提出反应性星形胶质细胞通过过量释放GABA在帕金森病病理过程中起关键作用。这种异常的星形胶质细胞GABA是由单胺氧化酶B（MAOB）的酶促作用合成的，据报道，其药理学抑制和基因沉默可显著减轻帕金森病动物模型中的帕金森运动症状。然而，MAOB的基因敲除和过表达是否能双向调节帕金森运动症状尚未得到验证。在此，我们证明，MAOB的基因敲除可阻断MPTP诱导的星形胶质细胞GABA介导的对邻近多巴胺能神经元的紧张性抑制以及帕金森运动症状，这表明MAOB对帕金森运动症状是必需的。此外，我们证明，GFAP-MAOB转基因小鼠（其中MAOB在GFAP启动子控制下过表达，实现星形胶质细胞特异性过表达）与野生型小鼠相比，表现出MPTP诱导的紧张性抑制和帕金森运动症状加剧，这表明星形胶质细胞MAOB对帕金森运动症状很重要。我们的研究为星形胶质细胞MAOB依赖性紧张性GABA合成的病理作用与帕金森运动症状之间的因果关系提供了遗传学证据。
