A monoclonal antibody targeting the C-terminal of α-synuclein fibrils mitigates pathology in a Parkinson's disease model

  • Cell Rep. 2026 Feb 24;45(2):116897. doi: 10.1016/j.celrep.2025.116897.
Shuyi Zeng  1 ,  Shengnan Zhang  2 ,  Xun Gui  3 ,  Danni Li  2 ,  Shiran Lv  4 ,  Hui Dong  4 ,  Qianhui Xu  4 ,  Jian Wu  3 ,  Hongyuan Ren  3 ,  Qinyue Zhao  1 ,  Houfang Long  4 ,  Yifan Yu  5 ,  Shouqiao Hou  4 ,  Weidong Le  6 ,  Mengqi Fan  3 ,  Datao Liu  7 ,  Dan Li  8 ,  Cong Liu  9
Affiliations
  • 1. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China; Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 2. Interdisciplinary Research Center on Biology and Chemistry, State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China.
  • 3. Mabwell (Shanghai) Bioscience Co., Ltd., Shanghai 201210, China.
  • 4. Interdisciplinary Research Center on Biology and Chemistry, State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; University of the Chinese Academy of Sciences, 19 A Yuquan Road, Shijingshan District, Beijing 100049, China.
  • 5. Shanghai Starriver Bilingual School, Shanghai 201108, China.
  • 6. Department of Neurology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China.
  • 7. Mabwell (Shanghai) Bioscience Co., Ltd., Shanghai 201210, China. Electronic address: [email protected].
  • 8. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China; Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: [email protected].
  • 9. Interdisciplinary Research Center on Biology and Chemistry, State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; Shanghai Academy of Natural Sciences (SANS), Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China. Electronic address: [email protected].
PMID: 41575853 DOI: 10.1016/j.celrep.2025.116897
Abstract

Parkinson's disease (PD) pathogenesis is driven by α-synuclein (α-syn) amyloid aggregation, with the flexible C-terminal region mediating pathological interactions with cellular receptors and facilitating disease propagation and neuroinflammation. Through immunization with human α-syn fibrils and iterative neuronal binding and propagation assays, we identify H21 as a high-affinity fibril-specific monoclonal antibody. H21 selectively binds to α-syn fibrils and specifically targets the C-terminal region. H21 competitively blocks interactions between α-syn fibrils and established receptors and binding partners, including FAM171A2, RAGE, LAG3, and LC3B. Cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET) studies reveal that H21 engages α-syn fibrils in a periodic manner, inducing conformational remodeling in the fibril architecture. In a PD mouse model, H21 treatment reduces pathological α-syn spreading, suppresses neuroinflammation, and significantly improves motor outcomes. These findings underscore the rational design and therapeutic potential of fibril-specific antibodies targeting the C-terminal region of α-syn to halt PD progression.

Keywords
CP: Neuroscience; Parkinson’s disease pathology; cryo-EM/ET structural determination; monoclonal antibody; passive immunotherapy; α-synuclein fibril-antibody complex; α-synuclein fibrils; α-synuclein fibril–specific antibody.
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