Conformation-specific Antibodies Targeting Aggregated Forms of α-synuclein Block the Propagation of Synucleinopathy

Abnormal aggregation of alpha-synuclein is a key element in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy. alpha-synuclein aggregation spreads through various brain regions during the course of disease progression, a propagation that is thought to be mediated by the secretion and subsequent uptake of extracellular alpha-synuclein aggregates between neuronal cells. Thus, aggregated forms of this protein have emerged as promising targets for disease-modifying therapy for PD and related diseases. Here, we generated and characterized conformation-specific antibodies that preferentially recognize aggregated forms of alpha-synuclein. These antibodies promoted phagocytosis of extracellular alpha-synuclein aggregates by microglial cells and interfered with cell-to-cell propagation of alpha-synuclein. In an alpha-synuclein transgenic model, passive immunization with aggregate-specific antibodies significantly ameliorated pathological phenotypes, reducing alpha-synuclein aggregation, gliosis, inflammation, and neuronal loss. These results suggest that conformation-specific antibodies targeting alpha-synuclein aggregates are promising therapeutic agents for PD and related synucleinopathies.

Automated summary

Abnormal aggregation of alpha-synuclein is a key factor in the progression of neurodegenerative diseases. Antibodies targeting aggregated forms of alpha-synuclein show promising potential as therapeutic agents for Parkinson's disease and related synucleinopathies.