RESUMO
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.
Assuntos
Amiloide/genética , Mutação de Sentido Incorreto , Doenças do Sistema Nervoso/genética , Doença de Parkinson/genética , Agregação Patológica de Proteínas/genética , alfa-Sinucleína/genética , Amiloide/metabolismo , Amiloide/ultraestrutura , Animais , Microscopia Crioeletrônica , Modelos Animais de Doenças , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia de Força Atômica , Microscopia Confocal , Atividade Motora/genética , Atividade Motora/fisiologia , Doenças do Sistema Nervoso/metabolismo , Doença de Parkinson/metabolismo , Agregação Patológica de Proteínas/metabolismo , alfa-Sinucleína/química , alfa-Sinucleína/metabolismoRESUMO
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.