Heparin induces α-synuclein to form new fibril polymorphs with attenuated neuropathology

作者：Youqi Tao, Yunpeng Sun, Shiran Lv, Wencheng Xia, Kun Zhao, Qianhui Xu, Qinyue Zhao, Lin He, Weidong Le, Yong Wang, Cong Liu, Dan Li · 发表于：Nature Communications · 年份：2022 · DOI：10.1038/s41467-022-31790-7 · 被引用次数：67 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Botulinum Toxin and Related Neurological Disorders、Alzheimer's disease research and treatments

α-Synuclein (α-syn), as a primary pathogenic protein in Parkinson's disease (PD) and other synucleinopathies, exhibits a high potential to form polymorphic fibrils. Chemical ligands have been found to involve in the assembly of α-syn fibrils in patients' brains. However, how ligands influence the fibril polymorphism remains vague. Here, we report the near-atomic structures of α-syn fibrils in complex with heparin, a representative glycosaminoglycan (GAG), determined by cryo-electron microscopy (cryo-EM). The structures demonstrate that the presence of heparin completely alters the fibril assembly via rearranging the charge interactions of α-syn both at the intramolecular and the inter-protofilamental levels, which leads to the generation of four fibril polymorphs. Remarkably, in one of the fibril polymorphs, α-syn folds into a distinctive conformation that has not been observed previously. Moreover, the heparin-α-syn complex fibrils exhibit diminished neuropathology in primary neurons. Our work provides the structural mechanism for how heparin determines the assembly of α-syn fibrils, and emphasizes the important role of biological polymers in the conformational selection and neuropathology regulation of amyloid fibrils.