ArticleBrain : a journal of neurology2024
MerTK is a mediator of alpha-synuclein fibril uptake by human microglia.
Article in Brain : a journal of neurology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 34 citations in OpenAlex.
- Article
- TFE3 Regulates Microglial Phagocytosis and Inflammation in MPTP-induced Parkinson's Disease.Molecular neurobiology · 2026Article
- Article
- Galectin-9 activates microglial asparagine endopeptidase and promotes α-synuclein pathology in Parkinson's disease.Cell death and differentiation · 2026Article
- Axonopathy: mechanisms and potential therapeutic targets for neurodegenerative diseases.Translational neurodegeneration · 2026Review
- Phagocytosis by retinal pigment epithelium and microglia does not affect vision restoration by P3HT nanoparticles in Retinitis pigmentosa.Cell death & disease · 2026Article
- Live cell imaging of exogenous α-synuclein fibrils in primary microglia and neuron co-cultures.Biochemistry and biophysics reports · 2026Article
- NLRP3/Caspase-1 Regulate Macrophage Efferocytosis by Modulating ADAM17-Mediated MerTK Cleavage in Liver Ischemia-Reperfusion Injury.Research (Washington, D.C.) · 2026Article
- ACOD1 regulates microglial arginine metabolism and inflammatory responses.Frontiers in immunology · 2026Article
- Flavonoid-rich dietary patterns and incident hospital-recorded Parkinson's disease: a prospective UK Biobank study.Frontiers in nutrition · 2026Article
- Integrating Genomic, eQTL, and Mendelian Randomization Analyses to Identify Microglial Drug Targets in Multiple Sclerosis.Journal of cellular and molecular medicine · 2025Article
- Novel regulators of heparan sulfate proteoglycans modulate cellular uptake of α-synuclein fibrils.Communications biology · 2025Article
- Extracellular LCN2 Binding to 24p3R in Astrocytes Impedes α-Synuclein Endocytosis in Parkinson's Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Parietal Lobe Epilepsy Associated With 2q13 Duplication: Expanding the Neurogenetic Spectrum.Cureus · 2025Article
- Opposing role of phagocytic receptors MERTK and AXL in Progranulin deficient FTD.Communications biology · 2025Article
- ADNP is essential for sex-dependent hippocampal neurogenesis, through male unfolded protein response and female mitochondrial gene regulation.Molecular psychiatry · 2025Article
- Irisin suppressed the progression of TBI via modulating AMPK/MerTK/autophagy and SYK/ROS/inflammatory signaling.Scientific reports · 2025Article
- The Influence of Changes in Microglia Development on the Plasticity of the Developing Visual Cortex Circuit in Juvenile Mice.Investigative ophthalmology & visual science · 2025Article
- Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson's disease.Cell reports · 2025Article
- Review
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Authors and funding
20 authors at 4 institutions in 3 countries.
Funding
Abstract
Mer tyrosine kinase (MerTK) is a receptor tyrosine kinase that mediates non-inflammatory, homeostatic phagocytosis of diverse types of cellular debris. Highly expressed on the surface of microglial cells, MerTK is of importance in brain development, homeostasis, plasticity and disease. Yet, involvement of this receptor in the clearance of protein aggregates that accumulate with ageing and in neurodegenerative diseases has yet to be defined. The current study explored the function of MerTK in the microglial uptake of alpha-synuclein fibrils which play a causative role in the pathobiology of synucleinopathies. Using human primary and induced pluripotent stem cell-derived microglia, the MerTK-dependence of alpha-synuclein fibril internalization was investigated in vitro. Relevance of this pathway in synucleinopathies was assessed through burden analysis of MERTK variants and analysis of MerTK expression in patient-derived cells and tissues. Pharmacological inhibition of MerTK and siRNA-mediated MERTK knockdown both caused a decreased rate of alpha-synuclein fibril internalization by human microglia. Consistent with the non-inflammatory nature of MerTK-mediated phagocytosis, alpha-synuclein fibril internalization was not observed to induce secretion of pro-inflammatory cytokines such as IL-6 or TNF, and downmodulated IL-1β secretion from microglia. Burden analysis in two independent patient cohorts revealed a significant association between rare functionally deleterious MERTK variants and Parkinson's disease in one of the cohorts (P = 0.002). Despite a small upregulation in MERTK mRNA expression in nigral microglia from Parkinson's disease/Lewy body dementia patients compared to those from non-neurological control donors in a single-nuclei RNA-sequencing dataset (P = 5.08 × 10-21), no significant upregulation in MerTK protein expression was observed in human cortex and substantia nigra lysates from Lewy body dementia patients compared to controls. Taken together, our findings define a novel role for MerTK in mediating the uptake of alpha-synuclein fibrils by human microglia, with possible involvement in limiting alpha-synuclein spread in synucleinopathies such as Parkinson's disease. Upregulation of this pathway in synucleinopathies could have therapeutic values in enhancing alpha-synuclein fibril clearance in the brain.
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