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Aggregated α‐synuclein activates microglia: a process leading to disease progression in Parkinson's disease
Abstract
A growing body of evidence indicates that an inflammatory process in the substantia nigra, characterized by activation of resident microglia, likely either initiates or aggravates nigral neurodegeneration in Parkinson's disease (PD). To study the mechanisms by which nigral microglia are activated in PD, the potential role of alpha-synuclein (a major component of Lewy bodies that can cause neurodegeneration when aggregated) in microglial activation was investigated. The results demonstrated that in a primary mesencephalic neuron-glia culture system, extracellular aggregated human alpha-synuclein indeed activated microglia; microglial activation enhanced dopaminergic neurodegeneration induced by aggregated alpha-synuclein. Furthermore, microglial enhancement of alpha-synuclein-mediated neurotoxicity depended on phagocytosis of alpha-synuclein and activation of NADPH oxidase with production of reactive oxygen species. These results suggest that nigral neuronal damage, regardless of etiology, may release aggregated alpha-synuclein into substantia nigra, which activates microglia with production of proinflammatory mediators, thereby leading to persistent and progressive nigral neurodegeneration in PD. Finally, NADPH oxidase could be an ideal target for potential pharmaceutical intervention, given that it plays a critical role in alpha-synuclein-mediated microglial activation and associated neurotoxicity.
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“In some in vitro experiments, misfolded α-synuclein showed no toxicity to neurons unless microglia were present, indicating that microglia activation may be crucial for the toxicity of α-synuclein aggregates to neurons.54,55”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [54]
In the citing paper
“release O 2 ⅐Ϫ or O 2 ⅐Ϫ -derived hydrogen peroxide when exposed to LPS, opsonized zymosan, or aggregated proteins that accumulate in the brain during neurodegenerative diseases (Sankarapandi et al., 1998;Zhang et al., 2005;B. Qin et al., 2006;Wilkinson et al., 2006).”
From Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase (2008) · cites this paper as Zhang et al., 2005
In the citing paper
“One prevailing theory to explain synucleinopathies is that progressive alterations in the microenvironment of microglia, such as increased deposition of α-synuclein, can change microglial behavior and function (Zhang et al., 2005; Su et al., 2008).”
From Microbiome–microglia connections via the gut–brain axis (2019) · cites this paper as Zhang et al., 2005
In the citing paper
“The sustained activation of microglia due to external cues from both misfolded α-synuclein and damaged neurons likely instigates a cycle of chronic inflammation that further perpetuates the death of dopaminergic neurons and accelerates progression of the disease (Zhang et al., 2005; Kim and Joh, 2006).”
From Microbiome–microglia connections via the gut–brain axis (2019) · cites this paper as Zhang et al., 2005
In the citing paper
“Heightened microglial activation results in the release of pro-inflammatory cytokines (e.g., IL-6 and TNF-α) and a variety of other neurotoxic compounds into their immediate extracellular environment (Zhang et al., 2005; Kim and Joh, 2006).”
From Microbiome–microglia connections via the gut–brain axis (2019) · cites this paper as Zhang et al., 2005
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Metadata
- Authors
- Zhang, W., Wang, T., Pei, Z., Miller, D. S., Wu, X., Block, M. L., Wilson, B., Zhang, W., Zhou, Y., Hong, J.-S., & Zhang, J.
- Affiliations
- National Institutes of Health (US)
- Dalian Medical University (CN)
- University of Washington (US)
- ORCID
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2005-04
- Volume
- 19
- Issue
- 6
- Pages
- 533-542
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2128631317
- Cited by
- 1,265
- References
- 50
- Citations by year
- 2026: 30 · 2025: 57 · 2024: 95 · 2023: 51 · 2022: 97 · 2021: 80 · 2020: 69 · 2019: 76 · 2018: 85 · 2017: 51 · 2016: 59 · 2015: 71 · 2014: 67 · 2013: 60 · 2012: 69
- FWCI
- 23.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Keywords
- alpha-synuclein aggregation, microglial activation, Parkinson's disease, substantia nigra, dopaminergic neuron loss, NADPH oxidase, reactive oxygen species, phagocytosis, neuroinflammation, Lewy bodies, neurotoxicity, disease progression
- MeSH terms
- Animals, Astrocytes, Brain, Cells, Cultured, Dopamine, Embryo, Mammalian, Enzyme Activation, gamma-Aminobutyric Acid, Humans, Immunohistochemistry, Mesencephalon, Nerve Degeneration, Neuroglia, Neurons, Nitric Oxide, Nitrites, Parkinson Disease, Phagocytosis, Polymers, Rats, Inbred F344, Recombinant Proteins, Substantia Nigra, Tritium, Tumor Necrosis Factor-alpha, Tyrosine 3-Monooxygenase, Dinoprostone, Reactive Oxygen Species, Microglia, Mice, Knockout, Oxidative Stress, NADPH Oxidases, Mice, Rats, alpha-Synuclein
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