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

Shuyi Zeng, Xingyu Xiong, Houfang Long, Qianhui Xu, Yifan Yu, Bo Sun, Cong Liu, Zhizhi Wang, Wenqing Xu, Shengnan Zhang and Dan Li ()
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Shuyi Zeng: Shanghai Jiao Tong University
Xingyu Xiong: ShanghaiTech University
Houfang Long: Chinese Academy of Sciences
Qianhui Xu: Chinese Academy of Sciences
Yifan Yu: Shanghai Starriver Bilingual School
Bo Sun: ShanghaiTech University
Cong Liu: Chinese Academy of Sciences
Zhizhi Wang: ShanghaiTech University
Wenqing Xu: ShanghaiTech University
Shengnan Zhang: Chinese Academy of Sciences
Dan Li: Shanghai Jiao Tong University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62755-1

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