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KMID : 0892920220310010029
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Experimental Neurobiology
2022 Volume.31 No. 1 p.29 ~ p.41
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Conformation-specific Antibodies Targeting Aggregated Forms of α-synuclein Block the Propagation of Synucleinopathy
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Choi Min-Sun
Kim Tae-Kyung
Ahn Jin-Hyung
Lee Jun-Sung
Jung Byung-Chul
An Sung-Won
Kim Dong-In
Lee Min-Jae
Mook-Jung Inhee
Lee Sang-Hoon
Lee Seung-Jae
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Abstract
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Abnormal aggregation of α-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. α-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 α-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 α-synuclein. These antibodies promoted phagocytosis of extracellular α-synuclein aggregates by microglial cells and interfered with cell-to-cell propagation of α-synuclein. In an α-synuclein transgenic model, passive immunization with aggregate-specific antibodies significantly ameliorated pathological phenotypes, reducing α-synuclein aggregation, gliosis, inflammation, and neuronal loss. These results suggest that conformation-specific antibodies targeting α-synuclein aggregates are promising therapeutic agents for PD and related synucleinopathies.
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KEYWORD
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Parkinson’s disease, Immunotherapy, Synuclein, Microglia
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