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

The Cryo-EM structures reported in this work reveal how heparin incorporates into alpha-syn fibril formation to determine fibril polymorphs. This highlights the role of biological polymers in the conformational selection and neuropathological regulation of amyloid fibrils. alpha-Synuclein (alpha-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 alpha-syn fibrils in patients' brains. However, how ligands influence the fibril polymorphism remains vague. Here, we report the near-atomic structures of alpha-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 alpha-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, alpha-syn folds into a distinctive conformation that has not been observed previously. Moreover, the heparin-alpha-syn complex fibrils exhibit diminished neuropathology in primary neurons. Our work provides the structural mechanism for how heparin determines the assembly of alpha-syn fibrils, and emphasizes the important role of biological polymers in the conformational selection and neuropathology regulation of amyloid fibrils.