Danzer Karin M, Krebs Simon K, Wolff Michael, Birk Gerald, Hengerer Bastian
CNS Research Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
J Neurochem. 2009 Oct;111(1):192-203. doi: 10.1111/j.1471-4159.2009.06324.x. Epub 2009 Aug 4.
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.
路易小体是α-突触核蛋白（α-syn）免疫阳性的细胞内沉积物，是帕金森病（PD）的病理标志。有趣的是，在将胎儿组织移植到PD患者纹状体中约十年后，在移植组织中发现了路易小体样结构。移植组织中α-syn加速沉积的一种可能解释是，α-syn从宿主组织到移植组织的聚集通过一种类似朊病毒疾病的机制传播。我们在此讨论一种体外模型，该模型可能概括了PD疾病传播的某些方面。我们发现，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聚集的跨膜播种。在原代神经元培养物以及神经元细胞系中均观察到了这种效应。播种寡聚体的特征是具有独特的十二烷基硫酸锂稳定寡聚体模式，并且可以在一个动态过程中由成孔寡聚体生成。我们提出，α-syn寡聚体形成为具有不同特性的寡聚体类型的动态混合物，并且α-syn寡聚体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。
