ArticleTranslational neurodegeneration2024
Astrocytes contribute to toll-like receptor 2-mediated neurodegeneration and alpha-synuclein pathology in a human midbrain Parkinson's model.
Article in Translational neurodegeneration, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed.
- Ultrashort wave therapy promotes traumatic brain injury recovery by suppressing neuroinflammation.Neural regeneration research · 2026Article
- Adcyap1r1-driven astrocyte reprogramming attenuates neuroinflammation and promotes dopaminergic neuroprotection in Parkinson's Disease.Stem cell research & therapy · 2026Article
- APOE4-Expressing Astrocytes Exhibit Parkinson's Disease-Related Pathology.Molecular neurobiology · 2026Article
- Sleep-circadian modulation of autophagy and glymphatic function: failure of coordinated brain clearance in Parkinson's disease.NPJ Parkinson's disease · 2026Review
- Using iPSC models to examine neuron-glia interactions in neurodegenerative diseases.Bioscience reports · 2026Review
- Integrative analysis via bioinformatics and machine learning identifies SERPING1 as a biomarker candidate for major depressive disorder.BMC psychiatry · 2026Article
- Anti-TLR2 immunotherapy modulates neuron-to-oligodendrocyte propagation of α-synuclein in mouse and human models.Nature communications · 2026Article
- Microglia, Astrocytes, and Oligodendrocytes in Parkinson's Disease: Neuroinflammatory Crosstalk and Emerging Therapeutic Strategies.Biomolecules · 2026Review
- Toll-like receptors in innate immunity and inflammation: from fundamental biology to clinic insights.Immunity & inflammation · 2026Review
- Lipid metabolism in microglia: Emerging mechanisms and therapeutic opportunities for neurodegenerative diseases (Review).International journal of molecular medicine · 2025Review
- Review
- Recent Advances in Autophagy and Immunotherapy for the Clearance of Aggregated α-Synuclein in Parkinson's Disease.Aging and disease · 2025Review
- Astrocytic and microglial cell functions in neuroinflammatory diseases and their animal models.Frontiers in cellular neuroscience · 2025Review
- The role of autophagy in synucleinopathy: clearance versus spread of α-synuclein.Autophagy reports · 2025Review
- The dual nature of neuroinflammation in networked brain.Frontiers in immunology · 2025Review
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6 authors.
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Abstract
backgroundParkinson's disease (PD) is characterised by degeneration of ventral midbrain dopaminergic (DA) neurons and abnormal deposition of α-synuclein (α-syn) in neurons. Activation of the innate immune pathogen recognition receptor toll-like receptor 2 (TLR2) is associated with exacerbation of α-syn pathology. TLR2 is increased on neurons in the PD brain, and its activation results in the accumulation and propagation of α-syn through autophagy inhibition in neurons. In addition to the aggregation and propagation of pathological α-syn, dysfunction of astrocytes may contribute to DA neuronal death and subsequent clinical progression of PD. However, the role of astrocytes in TLR2-mediated PD pathology is less explored but important to address, given that TLR2 is a potential therapeutic target for PD.
methodsInduced pluripotent stem cells from three controls and three PD patients were differentiated into a midbrain model comprised of neurons (including DA neurons) and astrocytes. Cells were treated with or without the TLR2 agonist Pam3CSK4, and α-syn pathology was seeded using pre-formed fibrils. Confocal imaging was used to assess lysosomal function and α-syn pathology in the different cell types, as well as DA neuron health and astrocyte activation.
resultsTLR2 activation acutely impaired the autophagy lysosomal pathway, and potentiated α-syn pathology seeded by pre-formed fibrils in PD neurons and astrocytes, leading to degeneration and loss of DA neurons. The astrocytes displayed impaired chaperone-mediated autophagy reducing their ability to clear accumulated α-syn, and increases of A1 neurotoxic phenotypic proteins SerpinG1, complement C3, PSMB8 and GBP2. Moreover, the phenotypic changes in astrocytes correlated with a specific loss of DA neurons.
conclusionsTaken together, these results support a role for astrocyte dysfunction in α-syn accumulation and DA neuronal loss following TLR2 activation in PD.
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