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

  • Nat Commun. 2025 Aug 9;16(1):7368. doi: 10.1038/s41467-025-62755-1.
Shuyi Zeng  1  2 ,  Xingyu Xiong  3 ,  Houfang Long  4  5 ,  Qianhui Xu  4  5 ,  Yifan Yu  6 ,  Bo Sun  3 ,  Cong Liu  4  7  8  9 ,  Zhizhi Wang  3 ,  Wenqing Xu  3 ,  Shengnan Zhang  4  7 ,  Dan Li  10  11
Affiliations
  • 1. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
  • 2. Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai, China.
  • 3. School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 4. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 5. University of the Chinese Academy of Sciences, Beijing, China.
  • 6. Shanghai Starriver Bilingual School, Shanghai, China.
  • 7. State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 8. Shanghai Academy of Natural Sciences (SANS), Fudan University, Shanghai, China.
  • 9. Shanghai Key Laboratory of Aging Studies, Shanghai, China.
  • 10. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China. [email protected].
  • 11. Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai, China. [email protected].
PMID: 40783395 DOI: 10.1038/s41467-025-62755-1
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.

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