Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche (UMR) S975, Institut du Cerveau et de la Moelle Epinière, Paris, France; Institut National de la Santé et de la Recherche Médicale, U975, Paris, France; and Centre National de la Recherche Scientifique, UMR 7225, Paris, France.
Mol Pharmacol. 2013 Dec;84(6):888-98. doi: 10.1124/mol.113.087965. Epub 2013 Sep 27.
Previous studies on postmortem human brain tissue have shown that the iron-binding glycoprotein lactoferrin is upregulated in dopamine (DA) neurons resistant to degeneration in Parkinson disease (PD). To study how this could possibly relate to disease progression, we used midbrain cultures and experimental settings that model the progressive loss of DA neurons in this disorder. Human lactoferrin of either recombinant or natural origin provided robust protection to vulnerable DA neurons in a culture paradigm in which these neurons die spontaneously and selectively as they mature. The efficacy of lactoferrin was comparable to that of glial cell line-derived neurotrophic factor, a prototypical neurotrophic factor for DA neurons. Neuroprotection by lactoferrin was attributable to its binding to heparan sulfate proteoglycans on the cell surface of DA neurons and subsequently to partial inactivation of focal adhesion kinase (FAK), a major effector kinase of integrins. We established that FAK inactivation served to unmask a prosurvival phosphoinositide 3-kinase/AKT-dependent signaling pathway that stimulates calcium shuttling from endoplasmic reticulum to mitochondria. DA neurons exposed to the mitochondrial toxin 1-methyl-4-phenylpyridinium were also partially protected by lactoferrin, further supporting the view that mitochondria may represent a downstream target for lactoferrin protective actions. Finally, we found that the iron binding capability of lactoferrin intervened in DA cell rescue only when neurodegeneration was consecutive to iron-catalyzed oxidative stress. Overall, our data suggest that the accumulation of lactoferrin in PD brains might be evidence of an attempt by the brain to minimize the consequences of neurodegeneration.
先前的研究表明，在帕金森病（PD）中对多巴胺（DA）神经元具有抗变性作用的铁结合糖蛋白乳铁蛋白在死后人脑组织中上调。为了研究这可能与疾病进展有何关系，我们使用了中脑培养物和实验设置，模拟了这种疾病中 DA 神经元的进行性丧失。重组或天然来源的人乳铁蛋白在一种培养模型中为易受伤害的 DA 神经元提供了强大的保护作用，在这种模型中，随着神经元的成熟，这些神经元会自发且选择性地死亡。乳铁蛋白的功效可与胶质细胞系衍生的神经营养因子（DA 神经元的典型神经营养因子）相媲美。乳铁蛋白的神经保护作用归因于其与 DA 神经元细胞表面的硫酸乙酰肝素蛋白聚糖的结合，随后部分失活粘着斑激酶（FAK），这是整合素的主要效应激酶。我们确定，FAK 失活作用揭示了一种促生存的磷酸肌醇 3-激酶/AKT 依赖性信号通路，该通路刺激钙从内质网向线粒体转移。暴露于线粒体毒素 1-甲基-4-苯基吡啶（1-methyl-4-phenylpyridinium）的 DA 神经元也部分受到乳铁蛋白的保护，这进一步支持了线粒体可能是乳铁蛋白保护作用的下游靶标的观点。最后，我们发现，只有在铁催化的氧化应激导致神经退行性变时，乳铁蛋白的铁结合能力才会干预 DA 细胞的挽救。总体而言，我们的数据表明，PD 大脑中乳铁蛋白的积累可能是大脑试图减轻神经退行性变后果的证据。
