Seeding induced by α-synuclein oligomers provides evidence for spreading of α-synuclein pathology
Seeding induced by α-synuclein oligomers provides evidence for spreading of α-synuclein pathology
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DOI：
10.1111/j.1471-4159.2009.06324.x
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发表时间：
2009-10-01
影响因子：
4.7
通讯作者：
Hengerer, Bastian
中科院分区：
文献类型：
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作者：
Danzer, Karin M.;Krebs, Simon K.;Hengerer, Bastian
路易体，α-突触核蛋白（α-syn）免疫阳性细胞内沉积物，是帕金森病（PD）的病理标志。有趣的是，在移植到PD患者的纹状体后约十年，已在胎儿组织移植物中鉴定出Lewybody样结构。对于alpha-syn在移植物中加速沉积的一种可能的解释是，从宿主组织到移植物的alpha-syn聚集通过朊病毒疾病样机制传播。我们在这里讨论一个体外模型，它可能概括疾病传播的某些方面在PD。我们在此发现，体外生成的α-syn寡聚体以剂量和时间依赖性方式诱导α-syn聚集的跨膜接种。在原代神经元培养物以及神经元细胞系中观察到这种效应。种子低聚物的特征在于独特的十二烷基硫酸锂稳定的低聚物模式，并且可以在动态过程中由成孔低聚物产生。我们提出，α-syn低聚物形成为具有不同性质的低聚物类型的动态混合物，并且α-syn低聚物可以根据脑环境条件转化为不同类型。我们的数据表明，细胞外α-syn寡聚体可以诱导细胞内α-syn聚集，因此我们假设类似的机制可能导致α-syn病理传播。
Lewy bodies, alpha-synuclein (alpha-syn) immunopositive intracellular deposits, are the pathological hallmark of Parkinson's disease (PD). Interestingly, Lewybody-like structures have been identified in fetal tissue grafts about one decade after transplantation into the striatum of PD patients. One possible explanation for the accelerated deposition of alpha-syn in the graft is that the aggregation of alpha-syn from the host tissue to the graft is spread by a prion disease-like mechanism. We discuss here an in vitro model which might recapitulate some aspects of disease propagation in PD. We found here that in vitro-generated alpha-syn oligomers induce transmembrane seeding of alpha-syn aggregation in a dose- and time-dependent manner. This effect was observed in primary neuronal cultures as well as in neuronal cell lines. The seeding oligomers were characterized by a distinctive lithium dodecyl sulfate-stable oligomer pattern and could be generated in a dynamic process out of pore-forming oligomers. We propose that alpha-syn oligomers form as a dynamic mixture of oligomer types with different properties and that alpha-syn oligomers can be converted into different types depending on the brain milieu conditions. Our data indicate that extracellular alpha-syn oligomers can induce intracellular alpha-syn aggregation, therefore we hypothesize that a similar mechanism might lead to alpha-syn pathology propagation.