Copper-Zinc Superoxide Dismutase (SOD1) Is Released by Microglial Cells and Confers Neuroprotection against 6-OHDA Neurotoxicity
Copper-Zinc Superoxide Dismutase (SOD1) Is Released by Microglial Cells and Confers Neuroprotection against 6-OHDA Neurotoxicity
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DOI：
10.1159/000337115
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发表时间：
2012-05
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影响因子：
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通讯作者：
E. Polazzi;Ilaria Mengoni;M. Caprini;Emiliano Pena-Altamira;E. Kurtys;Barbara Monti
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文献类型：
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作者：
E. Polazzi;Ilaria Mengoni;M. Caprini;Emiliano Pena-Altamira;E. Kurtys;Barbara Monti
小胶质细胞与神经元之间的相互作用对脑生理病理至关重要。在这个框架下，最近的数据已经将小胶质细胞的概念从本质上的巨噬细胞转变为通过释放神经保护分子来维持神经元稳态和功能的关键元素。通过蛋白质组学分析，我们确定了铜锌超氧化物歧化酶（SOD1）是由培养的大鼠初级小胶质细胞产生和释放的一种蛋白质。小胶质细胞来源的SOD1具有神经保护作用的证据来自初级小脑颗粒神经元（CGNs）暴露于多巴胺能毒素6-羟多巴胺（6-OHDA）的实验。在SOD1积累的小胶质条件培养基中，可以保护cgn免受变性，而SOD1抑制剂则可以消除神经保护作用。当外源SOD1添加到非条件培养基中时，这些效应也被复制。SOD1的神经保护作用是由外部来源的细胞钙增加介导的。进一步的实验表明，与其他类型的神经毒性挑战相比，SOD1对6-OHDA的神经保护具有特异性。SOD1由小胶质细胞通过溶酶体分泌途径组成性地产生和释放，首次被确定为小胶质细胞介导的神经保护的重要组成部分。这一新发现有助于进一步研究小胶质细胞介导的神经保护在神经退行性疾病体内模型中的作用。
Microglial-neuronal interactions are essential for brain physiopathology. In this framework, recent data have changed the concept of microglia from essentially macrophagic cells to crucial elements in maintaining neuronal homeostasis and function through the release of neuroprotective molecules. Using proteomic analysis, here we identify copper-zinc superoxide dismutase (SOD1) as a protein produced and released by cultured rat primary microglia. Evidence for a neuroprotective role of microglia-derived SOD1 resulted from experiments in which primary cerebellar granule neurons (CGNs) were exposed to the dopaminergic toxin 6-hydroxydopamine (6-OHDA). Microglial conditioned medium, in which SOD1 had accumulated, protected CGNs from degeneration, and neuroprotection was abrogated by SOD1 inhibitors. These effects were replicated when exogenous SOD1 was added to a nonconditioned medium. SOD1 neuroprotective action was mediated by increased cell calcium from an external source. Further experiments demonstrated the specificity of SOD1 neuroprotection against 6-OHDA compared to other types of neurotoxic challenges. SOD1, constitutively produced and released by microglia through a lysosomal secretory pathway, is identified here for the first time as an essential component of neuroprotection mediated by microglia. This novel information is relevant to stimulating further studies of microglia-mediated neuroprotection in in vivo models of neurodegenerative diseases.