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 () and Dan Li ()
Additional contact information
Youqi Tao: Shanghai Jiao Tong University
Yunpeng Sun: Chinese Academy of Sciences
Shiran Lv: Chinese Academy of Sciences
Wencheng Xia: Chinese Academy of Sciences
Kun Zhao: Chinese Academy of Sciences
Qianhui Xu: Chinese Academy of Sciences
Qinyue Zhao: Shanghai Jiao Tong University
Lin He: Shanghai Jiao Tong University
Weidong Le: Sichuan Academy of Medical Sciences-Sichuan Provincial Hospital
Yong Wang: Zhejiang University
Cong Liu: Chinese Academy of Sciences
Dan Li: Shanghai Jiao Tong University

Nature Communications, 2022, vol. 13, issue 1, 1-9

Abstract: 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-022-31790-7 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31790-7

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-31790-7

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().