Activation of MyD88-dependent TLR1/2 signaling by misfolded α-synuclein, a protein linked to neurodegenerative disorders
Open accessAbstract
Patients with neurodegenerative disorders called synucleinopathies may benefit from drugs that inhibit inflammatory receptors on microglia in the brain.
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CU-CPT22, a small molecule that specifically inhibits TLR1 and TLR2 receptors, reduced activation of NF-κB pathway and secretion of IL-1β and TNF-α in vitro, and ameliorated motor and sensory function in MPTP-induced PD mouse model in vivo.
“CU-CPT22, a small molecule that specifically inhibits TLR1 and TLR2 receptors, reduced activation of the NF-κB pathway and secretion of the proinflammatory cytokines IL-1β and TNF-α in vitro,567 as well as ameliorated motor and sensory function in MPTP-induced PD mouse model in vivo.568”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [567]
The Results section (‘Pharmacological inhibition of TLR1/2 attenuates oligomeric α-synuclein-mediated effects’; page not provided) reports that CU-CPT22 reduced NF-κB nuclear translocation and TNF-α release in cultured microglia. It does not report a CU-CPT22-specific reduction in IL-1β secretion. The MPTP mouse-model claim is attached to a different citation (568), not this source (567). (LLM, conf=0.83)
Experimental — accuracy not yet measuredAlpha-synuclein activates microglia through the TLR1/2 heterodimer.
“α-Synuclein activates microglia through the TLR1/2 heterodimer (158).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [158]
High-ordered α-syn oligomers rather than monomers induced microglial activation identified by morphological changes and biochemical activation with increased pro-inflammatory cytokine secretion.
“They found that high-ordered oligomers rather than monomers induced microglial activation identified by both morphological changes from bipolar to amoeboid and biochemical activation profiles manifested with increased pro-inflammatory cytokines secretion.294”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [294]
Via a specific interaction with TLRs, misfolded α-syn directly activates microglia and promotes production and release of pro-inflammatory cytokines.
“The above evidence indicates that via a specific interaction with TLRs, the misfolded α-syn directly activates microglia and promotes the production and release of pro-inflammatory cytokines.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [294]
α-syn-induced microglial activation depends on TLRs 1/2 signaling and TLR4 signaling.
“The α-syn-induced microglial activation depends on TLRs 1/2 signaling294 and TLR4 signaling.246”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [294]
Activation of microglia by α-syn is also dependent on TLR1/2 signaling.
“Besides, the activation of microglia by α-syn was also dependent on TLR1/2 signaling,294”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [294]
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References 137 · Cited by 303
- Authors
- Daniele, S. G., Béraud, D., Davenport, C., Cheng, K., Yin, H., & Maguire-Zeiss, K. A.
- Affiliations
- Georgetown University Medical Center (US)
- University of Colorado Boulder (US)
- Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
- Corresponding author
- Yin, Hang
- Venue
- Science Signaling
- Published
- 2015-05-12
- Volume
- 8
- Issue
- 376
- Pages
- ra45-ra45
- ISSN
- 1937-9145 (ISSN-L)
- 1945-0877
- PMC
- PMC4601639
- OpenAlex
- W2117175402
- Cited by
- 303
- References
- 137
- Citations by year
- 2026: 19 · 2025: 21 · 2024: 34 · 2023: 23 · 2022: 37 · 2021: 47 · 2020: 37 · 2019: 25 · 2018: 23 · 2017: 17 · 2016: 13 · 2015: 7
- FWCI
- 10.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Signaling (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Parkinson's Disease Foundation Summer Student Fellowship (PDF-SFW-1350)
- NIH/National Institute of Neurological Disorders and Stroke (T32NS041218)
- NIH (R01GM101279)
- NIH/National Institute of Environmental Health Sciences (R01ES014470)
- Parkinson's Movement Disorder Foundation
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- alpha-synuclein, TLR1/2, MyD88, synucleinopathies, Parkinson's disease, dementia with Lewy bodies, microglial activation, neuroinflammation, NF-κB nuclear translocation, TNF-α, IL-1β, oligomeric alpha-synuclein, candesartan cilexetil, drug repurposing, Toll-like receptor signaling
- MeSH terms
- Animals, Humans, Parkinson Disease, Signal Transduction, Protein Folding, Lewy Body Disease, Toll-Like Receptor 1, Toll-Like Receptor 2, Mice, alpha-Synuclein, Myeloid Differentiation Factor 88, Proteostasis Deficiencies, HEK293 Cells
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