Zeng Shuyi, Xiong Xingyu, Long Houfang, Xu Qianhui, Yu Yifan, Sun Bo, Liu Cong, Wang Zhizhi, Xu Wenqing, Zhang Shengnan, Li Dan
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.
Nat Commun. 2025 Aug 9;16(1):7368. doi: 10.1038/s41467-025-62755-1.
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.
帕金森病（PD）的特征是病理性α-突触核蛋白（α-syn）原纤维的积累和扩散，这会导致神经炎症和神经退行性变。在此，我们表明，源自α-syn受体的两个免疫球蛋白样（Ig样）结构域，即淋巴细胞激活基因3的D1结构域（L3D1）和晚期糖基化终产物的V结构域（vRAGE），可有效阻断α-syn原纤维与细胞表面的结合，抑制原纤维诱导的神经元α-syn聚集，并减少小胶质细胞中的炎症反应。在此基础上，我们鉴定出另外两种Ig样结合物，即分化簇4的D1结构域（CD4 D1）和嵌合抗原受体的D1结构域（CAR D1），它们靶向α-syn原纤维的C末端区域并减轻原纤维诱导的病理活性。一种结构导向的突变体CAR D1_Mut表现出增强的结合亲和力和功能效力。这些发现突出了Ig样结合物作为干扰病理性α-syn相互作用的分子工具的潜力。
