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Human microglia remove intraneuronal a-synuclein aggregates in a stem cell model of Parkinson’s disease

ABSTRACT: Microglia are the primary immune cells of the brain but their role in Parkinson’s disease is not fully understood. Although most studies suggest that chronic microglial activation is toxic to neurons, they also exert beneficial functions in the early stages of neuronal pathology that are not yet well defined. We used iPSC modelling to investigate how human microglia respond to α-synuclein aggregation that forms de novo in human dopaminergic neurons with α-synuclein gene triplication or is triggered by fibrils. We found that microglia cleared Ser129 phosphorylated α-synuclein aggregates without exacerbating neurotoxicity, using a contact-dependent mechanism involving selective phagocytosis (i.e. trogocytosis) of neuronal sub-compartments that is independent of TREM2 or phosphotidylserine. In the presence of intraneuronal α-synuclein aggregates, microglia exhibited morphological changes and transcriptomic profiles indicative of activation. Using single cell sequencing, we identified a sub-cluster of disease-associated microglia (DAM) in association with this phenotype, and GPNMB as a key effector of a-synuclein aggregate clearance by microglial lysosomes. Importantly, our secretome analysis suggests that the identified DAM sub-cluster is negatively regulated by an autocrine loop mechanism involving IL-10 and blocking this pathway using antibodies promotes the phagocytic response. Taken together, our study identifies a specific microglial subtype that exerts beneficial trogocytic effects on human dopaminergic neurons containing α-synuclein aggregates and suggests that stabilisation of such subpopulations during the neurodegenerative process could be a useful therapeutic strategy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290525 | GEO | 2026/07/15

REPOSITORIES: GEO

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Project description:Background: Cell-to-cell propagation of α-synuclein (α-syn) aggregates is thought to contribute to the pathogenesis of Parkinson’s disease (PD) and underlie the spread of α-syn neuropathology. Increased pro-inflammatory cytokine levels and activated microglia are present in PD and activated microglia can promote α-syn aggregation. However, it is unclear how microglia influence α-syn cell-to-cell transfer. Methods: We developed a clinically relevant mouse model to monitor α-syn prion-like propagation between cells; we transplanted wild-type mouse embryonic midbrain neurons into a mouse striatum overexpressing human α-syn (huα-syn) following adeno-associated viral injection into the substantia nigra. In this system, we depleted or activated microglial cells and determined the effects on the transfer of huα-syn from host nigrostriatal neurons into the implanted dopaminergic neurons, using the presence of huα-syn within the grafted cells as a readout. Results: First, we compared α-syn cell-to-cell transfer between host mice with a normal number of microglia to mice in which we had pharmacologically ablated 80% of the microglia from the grafted striatum. With fewer host microglia, we observed increased accumulation of huα-syn in grafted dopaminergic neurons. Second, we assessed the transfer of α-syn into grafted neurons in the context of microglia activated by one of two stimuli, lipopolysaccharide (LPS) or interleukin-4 (IL-4). LPS exposure led to a strong activation of microglial cells (as determined by microglia morphology and cytokine production) and significantly higher amounts of huα-syn in grafted neurons. In contrast, injection of IL-4 did not change the proportion of grafted dopamine neurons that contained huα-syn relative to controls. RNA sequencing analysis revealed differential gene expression between LPS and IL-4 injected mice; many genes were upregulated in LPS including those involved with the inflammatory response. Conclusions: The absence or the hyperstimulation of microglia affected α-syn transfer in the brain. Our results suggest that under resting, non-inflammatory conditions, microglia modulate the transfer of α-syn. Pharmacological regulation of neuroinflammation could represent a future avenue for limiting the spread of PD neuropathology.

Project description:Abnormal accumulation of aggregated proteins and sustained microglial activation are important contributors of neurodegenerative process in neurological diseases. Recent studies have shown that aggregation-prone proteins, such as a-synuclein, the protein implicated in Parkinson’s disease (PD), are released from neuronal cells and thus present in the extracellular fluid, pointing to the possible paracrine effects of these proteins on microglial immune responses. However, the mechanism underlying the disease-associated microglial activation and the role of neuronal proteins in this process remain unknown. Here, we show that extracellular a-synuclein released from neuronal cells is an endogenous ligand of toll-like receptor 2 (TLR2) and activates microglia, which in turn induces neurodegeneration. Interaction between neuron-released a-synuclein and TLR2 and subsequent activation of the TLR2 signaling were demonstrated comprehensively by using computational modeling of signaling network and by the experimental validation in TLR2-deficient microglia both in vitro and in vivo. In contrast to the neuron-released a-synuclein, recombinant a-synuclein proteins, including monomer, oligomer, fibril, or nitrated forms, were not able to interact or activate TLR2, suggesting that neuronal cells have a mechanism of enriching specific forms of a-synuclein capable of activating TLR2 during the process of releasing this protein. Taken together, the results suggest that both neuron-released extracellular a-synuclein and TLR2 might be novel therapeutic targets for modifying neuroinflammation in PD and related neurodegenerative diseases. We collected culture media from differentiated SH-SY5Y cells overexpressing either human a-synuclein (alpha-SCM) or beta-galactosidase (LZCM) and treat these media to primary rat microglia at the concentration of a-synuclein of 1.1M. Transcriptome analyses with microglial cells treated with either aSCM or LZCM at two different time points, 6 h and 24 h.

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Human microglia remove intraneuronal a-synuclein aggregates in a stem cell model of Parkinson’s disease

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