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

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

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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