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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月9日

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  • Shuyi Zeng,
  • Xingyu Xiong,
  • Houfang Long,
  • Qianhui Xu,
  • Yifan Yu,
  • Bo Sun,
  • Cong Liu,
  • Zhizhi Wang,
  • Wenqing Xu,
  • Shengnan Zhang,
  • Dan Li

摘要

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.