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

Youqi Tao, Yunpeng Sun, Shiran Lv, Wencheng Xia, Kun Zhao, Qianhui Xu, Qinyue Zhao, Lin He, Weidong Le, Yong Wang, Cong Liu, Dan Li

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number4226
Pages (from-to)4226
JournalNature Communications
Volume13
Issue number1
DOIs
StatePublished - Jul 22 2022

Keywords

  • Amyloid/metabolism
  • Cryoelectron Microscopy
  • Heparin
  • Humans
  • Protein Conformation
  • alpha-Synuclein/metabolism

ASJC Scopus subject areas

  • Physics and Astronomy(all)
  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint

Dive into the research topics of 'Heparin induces α-synuclein to form new fibril polymorphs with attenuated neuropathology'. Together they form a unique fingerprint.

Cite this