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Design of Ig-like binders targeting α-synuclein fibril for mitigating its pathological activities

Author

Listed:
  • Shuyi Zeng

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Xingyu Xiong

    (ShanghaiTech University)

  • Houfang Long

    (Chinese Academy of Sciences
    University of the Chinese Academy of Sciences)

  • Qianhui Xu

    (Chinese Academy of Sciences
    University of the Chinese Academy of Sciences)

  • Yifan Yu

    (Shanghai Starriver Bilingual School)

  • Bo Sun

    (ShanghaiTech University)

  • Cong Liu

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    Fudan University
    Shanghai Key Laboratory of Aging Studies)

  • Zhizhi Wang

    (ShanghaiTech University)

  • Wenqing Xu

    (ShanghaiTech University)

  • Shengnan Zhang

    (Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Dan Li

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

Abstract

Parkinson’s disease (PD) is characterized by the accumulation and spread of pathological α-synuclein (α-syn) fibrils, which contribute to neuroinflammation and neurodegeneration. Here we show that two immunoglobulin-like (Ig-like) domains derived from α-syn receptors, the D1 domain of lymphocyte-activation gene 3 (L3D1) and the V domain of advanced glycation end-products (vRAGE), effectively block cell surface binding of α-syn fibrils, suppress fibrils-induced neuronal α-syn aggregation, and reduce inflammatory responses in microglia. Building on this, we identified two additional Ig-like binders, the D1 domain of cluster of differentiation 4 (CD4 D1) and the D1 domain of chimeric antigen receptor (CAR D1), that target the C-terminal region of α-syn fibrils and mitigate fibrils-induced pathological activities. A structure-guided mutant, CAR D1_Mut, exhibits enhanced binding affinity and functional efficacy. These findings highlight the potential of Ig-like binders as molecular tools to interfere with pathological α-syn interactions.

Suggested Citation

  • Shuyi Zeng & Xingyu Xiong & Houfang Long & Qianhui Xu & Yifan Yu & Bo Sun & Cong Liu & Zhizhi Wang & Wenqing Xu & Shengnan Zhang & Dan Li, 2025. "Design of Ig-like binders targeting α-synuclein fibril for mitigating its pathological activities," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62755-1
    DOI: 10.1038/s41467-025-62755-1
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