2. Academic Validation
  3. Different charged biopolymers induce α-synuclein to form fibrils with distinct structures

Different charged biopolymers induce α-synuclein to form fibrils with distinct structures

  • J Biol Chem. 2024 Oct 5;300(11):107862. doi: 10.1016/j.jbc.2024.107862.
Yuxuan Yao 1,  Qinyue Zhao 1,  Youqi Tao 1,  Kaien Liu 2,  Tianyi Cao 3,  Zipeng Chen 4,  Cong Liu 2,  WeiDong Le 5,  Jing Zhao 4,  Dan Li 6,  Wenyan Kang 7
Affiliations

Affiliations

  • 1 Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China; Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai, China.
  • 2 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 3 School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
  • 4 Chemistry and Biomedicine Innovation Center (ChemBIC), State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China.
  • 5 Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
  • 6 Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China; Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai, China. Electronic address: lidan2017@sjtu.edu.cn.
  • 7 Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Neurology, Ruijin Hainan Hospital, Shanghai Jiao Tong University, School of Medicine (Boao Research Hospital), Hainan, China. Electronic address: kwy12697@rjh.com.cn.
PMID: 39374778 DOI: 10.1016/j.jbc.2024.107862
Abstract

The aggregation of α-synuclein (α-syn) into amyloid fibrils, a key process in the development of Parkinson's disease (PD) and Other synucleinopathies, is influenced by a range of factors such as charged biopolymers, chaperones, and metabolites. However, the specific impacts of different biopolymers on α-syn fibril structure are not well understood. In our work, we found that different polyanions and polycations, such as polyphosphate (polyP), polyuridine (polyU), and polyamines (including putrescine, spermidine, and spermine), markedly altered the fibrillation kinetics of α-syn in vitro. Furthermore, the seeding assay revealed distinct cross-seeding capacities across different biopolymer-induced α-syn fibrils, suggesting the formation of structurally distinct strains under different conditions. Utilizing cryo-electron microscopy (cryo-EM), we further examined the detailed structural configuration of α-syn fibrils formed in the presence of these biopolymers. Notably, we found that while polyamines do not change the atomic structure of α-syn fibrils, polyU and polyP induce the formation of distinct amyloid fibrils, exhibiting a range of structural polymorphs. Our work offers valuable insights into how various charged biopolymers affect the aggregation process and the resultant structures of α-syn fibrils, thereby enhancing our understanding of the structural variations in α-syn fibrils across different pathological conditions.

Keywords

Parkinson's disease; amyloid; charged biopolymers; cryo-EM structure; α-synuclein.

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