Protein fibrils drive the onset and progression of many diseases in a prion-like manner, i.e. they transcellular propagate through the extracellular space to health cells to initiate toxic aggregation as seeds. The conversion of native α-synuclein into filamentous aggregates in Lewy bodies is a hallmark of Parkinson's disease (PD). Copper and iron ions accumulate in PD brains, however, whether they influence the prion-like propagation of α-synuclein remain unclear. Here, we reported that copper/iron ions accelerate prion-like propagation of α-synuclein fibrils by promoting cellular internalization of α-synuclein fibrils, intracellular α-synuclein aggregation and the subsequent release of mature fibrils to the extracellular space to induce further propagation. Mechanistically, copper/iron ions enhanced α-synuclein fibrils internalization was mediated by negatively charged membrane heparan sulfate proteoglycans (HSPGs). α-Synuclein fibrils formed in the presence of copper/iron ions were more cytotoxic, causing increased ROS production, cell apoptosis, and shortened the lifespan of a C. elegans PD model overexpressing human α-synuclein. Notably, these deleterious effects were ameliorated by two clinically used chelators, triethylenetetramine and deferiprone. Together, our results suggest a new role for heavy metal ions, e.g. copper and iron, in the pathogenesis of PD through accelerating prion-like propagation of α-synuclein fibrils.

蛋白质原纤维以a病毒样的方式驱动许多疾病的发作和发展，即它们跨细胞通过细胞外空间传播到健康细胞，从而引发有毒的种子聚集。在路易体中天然α-突触核蛋白转化为丝状聚集体是帕金森氏病（PD）的标志。铜和铁离子在PD脑中积累，但是，它们是否影响α-突触核蛋白的the病毒样繁殖尚不清楚。在这里，我们报道铜/铁离子通过促进α-突触核蛋白原纤维的细胞内在化，细胞内α-突触核蛋白的聚集以及随后成熟纤维的释放到细胞外空间以诱导进一步的繁殖来加速α-突触核蛋白原纤维的病毒样繁殖。从机理上讲，铜/铁离子增强的α-突触核蛋白原纤维的内在化是由带负电荷的膜硫酸乙酰肝素蛋白聚糖（HSPG）介导的。秀丽隐杆线虫PD模型过表达人α-突触核蛋白。值得注意的是，两种临床上使用的螯合剂三亚乙基四胺和去铁酮可改善这些有害作用。总之，我们的结果表明，重金属离子（例如铜和铁）通过加速α-突触核蛋白原纤维的病毒样繁殖，在PD的发病机理中具有新的作用。