Heterozygous point mutations of α-synuclein (α-syn) have been linked to the early onset and rapid progression of familial Parkinson’s diseases (fPD). However, the interplay between hereditary mutant and wild-type (WT) α-syn and its role in the exacerbated pathology of α-syn in fPD progression are poorly understood. Here, we find that WT mice inoculated with the human E46K mutant α-syn fibril (hE46K) strain develop early-onset motor deficit and morphologically different α-syn aggregation compared with those inoculated with the human WT fibril (hWT) strain. By using cryo-electron microscopy, we reveal at the near-atomic level that the hE46K strain induces both human and mouse WT α-syn monomers to form the fibril structure of the hE46K strain. Moreover, the induced hWT strain inherits most of the pathological traits of the hE46K strain as well. Our work suggests that the structural and pathological features of mutant strains could be propagated by the WT α-syn in such a way that the mutant pathology would be amplified in fPD.

α-突触核蛋白 (α-syn) 的杂合点突变与家族性帕金森病 (fPD) 的早发和快速进展有关。然而，对遗传突变体和野生型 (WT) α-syn 之间的相互作用及其在 fPD 进展中 α-syn 恶化病理中的作用知之甚少。在这里，我们发现接种人 E46K 突变体 α-syn 原纤维 (hE46K) 菌株的 WT 小鼠与接种人 WT 原纤维 (hWT) 菌株的小鼠相比，会出现早发性运动缺陷和形态学上不同的 α-syn 聚集。通过使用低温电子显微镜，我们在近原子水平上揭示了 hE46K 菌株诱导人和小鼠 WT α-syn 单体形成 hE46K 菌株的原纤维结构。此外，诱导的 hWT 菌株也继承了 hE46K 菌株的大部分病理特征。