Conformation-specific Antibodies Targeting Aggregated Forms of α-synuclein Block the Propagation of Synucleinopathy
- Author:
Minsun CHOI
1
;
Tae-kyung KIM
;
Jinhyung AHN
;
Jun Sung LEE
;
Byung Chul JUNG
;
Sungwon AN
;
Dongin KIM
;
Min Jae LEE
;
Inhee MOOK-JUNG
;
Sang Hoon LEE
;
Seung-Jae LEE
Author Information
- Publication Type:Original Article
- From:Experimental Neurobiology 2022;31(1):29-41
- CountryRepublic of Korea
- Language:English
- Abstract: 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.
