Antibody-Aided Clearance of Extracellular α-Synuclein Prevents Cell-to-Cell Aggregate Transmission
Open accessAbstract
Abnormal deposition and intercellular propagation of α-synuclein plays a central role in the pathogenesis of disorders such as Parkinson's Disease (PD) and dementia with Lewy bodies (DLB). Previous studies demonstrated that immunization against α-synuclein resulted in reduced α-synuclein accumulation and synaptic loss in a transgenic (tg) mouse model, highlighting the potential for immunotherapy. However, the mechanism by which immunization prevents synucleinopathy-associated deficits remains unknown. Here, we show that antibodies against α-synuclein specifically target and aid in clearance of extracellular α-synuclein proteins by microglia, thereby preventing their actions on neighboring cells. Antibody-assisted clearance occurs mainly in microglia through the Fcγ receptor, and not in neuronal cells or astrocytes. Stereotaxic administration of antibody into the brains of α-synuclein tg mice prevented neuron-to-astroglia transmission of α-synuclein and led to increased localization of α-synuclein and the antibody in microglia. Furthermore, passive immunization with α-synuclein antibody reduced neuronal and glial accumulation of α-synuclein and ameliorated neurodegeneration and behavioral deficits associated with α-synuclein overexpression. These findings provide an underlying mechanistic basis for immunotherapy for PD/DLB and suggest extracellular forms of α-synuclein as potential therapeutic targets.
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Extracellular α-synuclein aggregates can interact with microglia via TLR2 to activate the LRRK2-NFATc2 pathway and produce a pro-inflammatory phenotype, and can also interact with other receptors to initiate LRRK2-dependent aggregate phagocytosis and clearance via lysosomal pathways.
“Extracellular α-synuclein aggregates may interact with microglia in at least two different ways: on one hand, they may stimulate TLR2 to activate the LRRK2-NFATc2 pathway and produce a pro-inflammatory phenotype, as shown in the present study; on the other, they can also interact with other receptors to initiate LRRK2-dependent aggregate phagocytosis (48) and clearance via lysosomal pathways (49,”
From LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies (2020) · cites this paper as [50]
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Self-citation
- Authors
- Bae, E.-J., Lee, H.-J., Rockenstein, E., Ho, D.-H., Park, E.-B., Yang, N.-Y., Desplats, P., Masliah, E., & Lee, S.-J.
- Affiliations
- Konkuk University (KR)
- University of California San Diego (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-09-26
- Volume
- 32
- Issue
- 39
- Pages
- 13454-13469
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3752153
- OpenAlex
- W2029319167
- Cited by
- 339
- References
- 10
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 19 · 2023: 21 · 2022: 27 · 2021: 21 · 2020: 28 · 2019: 33 · 2018: 24 · 2017: 26 · 2016: 31 · 2015: 33 · 2014: 27 · 2013: 27
- FWCI
- 18.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Research Foundation
- National Institutes of Health (AG‐022074, NS044233)
- National Institute on Aging (AG18840, AG-11385, R37AG018440, R37AG011385, AG022074, P01AG022074, R01AG011385)
- National Institute of Neurological Disorders and Stroke (P01NS044233, NS-044233)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- alpha-synuclein, antibody immunotherapy, microglia, Fc gamma receptor, Parkinson's disease, dementia with Lewy bodies, synucleinopathies, neurodegeneration, astroglia, transgenic mouse model
- MeSH terms
- Amyloid, Analysis of Variance, Animals, Antibodies, Astrocytes, Brain, Calcium-Binding Proteins, Cathepsin D, Cell Communication, Cell Line, Chromatography, Gel, Disease Models, Animal, Extracellular Space, Humans, Immunization, Passive, Mice, Transgenic, Microfilament Proteins, Nerve Degeneration, Synaptic Transmission, Neuroglia, Phosphopyruvate Hydratase, Platelet-Derived Growth Factor, Antigens, CD, Cytokines, Culture Media, Conditioned, Lewy Body Disease, Microscopy, Electron, Transmission, Caveolin 1, Mice, alpha-Synuclein
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