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.