Department of Biomedicine, Aarhus University, Aarhus, Denmark.
PLoS One. 2013;8(1):e55243. doi: 10.1371/journal.pone.0055243. Epub 2013 Jan 25.
Multiple system atrophy is a parkinsonian neurodegenerative disorder. It is cytopathologically characterized by accumulation of the protein p25α in cell bodies of oligodendrocytes followed by accumulation of aggregated α-synuclein in so-called glial cytoplasmic inclusions. p25α is a stimulator of α-synuclein aggregation, and coexpression of α-synuclein and p25α in the oligodendroglial OLN-t40-AS cell line causes α-synuclein aggregate-dependent toxicity. In this study, we investigated whether the FAS system is involved in α-synuclein aggregate dependent degeneration in oligodendrocytes and may play a role in multiple system atrophy. Using rat oligodendroglial OLN-t40-AS cells we demonstrate that the cytotoxicity caused by coexpressing α-synuclein and p25α relies on stimulation of the death domain receptor FAS and caspase-8 activation. Using primary oligodendrocytes derived from PLP-α-synuclein transgenic mice we demonstrate that they exist in a sensitized state expressing pro-apoptotic FAS receptor, which makes them sensitive to FAS ligand-mediated apoptosis. Immunoblot analysis shows an increase in FAS in brain extracts from multiple system atrophy cases. Immunohistochemical analysis demonstrated enhanced FAS expression in multiple system atrophy brains notably in oligodendrocytes harboring the earliest stages of glial cytoplasmic inclusion formation. Oligodendroglial FAS expression is an early hallmark of oligodendroglial pathology in multiple system atrophy that mechanistically may be coupled to α-synuclein dependent degeneration and thus represent a potential target for protective intervention.
多系统萎缩是一种帕金森神经退行性疾病。其病理特征为少突胶质细胞胞体内 p25α 蛋白堆积，随后出现所谓的神经胶质细胞胞质包涵体中聚集的α-突触核蛋白。p25α 是α-突触核蛋白聚集的刺激物，α-突触核蛋白和 p25α 在 OLN-t40-AS 少突胶质细胞系中的共表达会导致α-突触核蛋白聚集依赖性毒性。在这项研究中，我们研究了 FAS 系统是否参与少突胶质细胞中α-突触核蛋白聚集依赖性变性，以及是否在多系统萎缩中发挥作用。我们使用大鼠少突胶质细胞 OLN-t40-AS 细胞证明了共表达α-突触核蛋白和 p25α 引起的细胞毒性依赖于死亡结构域受体 FAS 的刺激和半胱天冬酶-8 的激活。使用源自 PLP-α-突触核蛋白转基因小鼠的原代少突胶质细胞，我们证明它们处于表达促凋亡 FAS 受体的敏感状态，这使它们对 FAS 配体介导的凋亡敏感。免疫印迹分析显示多系统萎缩病例的脑提取物中 FAS 增加。免疫组织化学分析显示，多系统萎缩脑内 FAS 表达增强，尤其是在最早出现神经胶质细胞质包涵体形成的少突胶质细胞中。少突胶质细胞 FAS 表达是多系统萎缩中少突胶质病理的早期标志，其机制可能与α-突触核蛋白依赖性变性有关，因此代表了潜在的保护干预靶点。
