BACKGROUND & AIMS:
: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.
背景与目标:
: 蛋白质原纤维以类似朊病毒的方式驱动许多疾病的发生和发展,即它们通过细胞外空间跨细胞传播到健康细胞,以启动作为种子的毒性聚集。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大脑中积累,但是,它们是否影响 α-突触核蛋白的朊病毒样传播尚不清楚。在这里,我们报道了铜/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-突触核蛋白聚集以及随后成熟原纤维释放到细胞外空间以诱导进一步繁殖来加速 α-突触核蛋白原纤维的病毒样传播。从机理上讲,铜/铁离子增强了 α-突触核蛋白原纤维的内在化是由带负电的膜硫酸乙酰肝素蛋白聚糖 (hspg) 介导的。在铜/铁离子存在下形成的 α-突触核蛋白原纤维更具细胞毒性,导致ROS产生增加,细胞凋亡并缩短了过度表达人类 α-突触核蛋白的秀丽隐杆线虫PD模型的寿命。值得注意的是,两种临床使用的螯合剂三乙烯四胺和去铁酮改善了这些有害作用。总之,我们的结果表明,通过加速 α-突触核蛋白原纤维的朊病毒样传播,重金属离子 (例如铜和铁) 在PD的发病机理中起新作用。