Design of Ig-like binders targeting α-synuclein fibril for mitigating its pathological activities
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.
Authors
- Xingyu Xiong (ORCID: https://orcid.org/0009-0002-7562-1066)
- Bo Sun (ORCID: https://orcid.org/0000-0002-4590-7795)
- Houfang Long (ORCID: https://orcid.org/0000-0002-1116-3185)
- Shengnan Zhang (ORCID: https://orcid.org/0009-0007-3465-7704)
- Shuyi Zeng
- Qianhui Xu (ORCID: https://orcid.org/0000-0002-9175-8532)
- Wenqing Xu (ORCID: https://orcid.org/0000-0002-2884-3101)
- Cong Liu (ORCID: https://orcid.org/0000-0003-3425-6672)
- Dan Li (ORCID: https://orcid.org/0000-0002-1609-1539)
- Zhizhi Wang (ORCID: https://orcid.org/0000-0003-4948-925X)
- Y. H. Yu (ORCID: https://orcid.org/0000-0003-1301-2716)
Institutions
- Shanghai Academy of Social Sciences (CN)
- Shanghai Jiao Tong University (CN)
- Chinese Academy of Sciences (CN)
- Fudan University (CN)
- ShanghaiTech University (CN)
- Shanghai Advanced Research Institute (CN)
- Shanghai Institute of Organic Chemistry (CN)
- Ministry of Education (TH)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-09
- DOI
- https://doi.org/10.1038/s41467-025-62755-1
- Citations
- 5
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 6.95
Funders
- National Science Foundation
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Science and Technology Commission of Shanghai Municipality
- Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
- Shanghai Advanced Research Institute, Chinese Academy of Sciences