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Differential microglial responses to structurally distinct alpha-synuclein polymorphs

ABSTRACT: Synucleinopathies are age-related neurological disorders which include dementia with Lewy bodies (DLB), Parkinson’s disease (PD), and multiple system atrophy (MSA). The diseases are characterized by the abnormal deposition and aggregation of a-synuclein and neuroinflammation. Recent studies have demonstrated the existence of structurally distinct a-synuclein aggregates in this group of the diseases. While the correlation between specific forms of a-synuclein and distinct pathological characteristics has been extensively studied, their relationship to neuroinflammation remains elusive. Here, we examined the effects of structurally distinct a-synuclein polymorphs on microglial neuroinflammation. Human induced pluripotent stem cells (iPSCs)-derived microglia (iMicroglia) were treated with a-synuclein polymorphs including EGCG stabilized a-synuclein oligomers (EO), kinetically stable a-synuclein oligomers (KSO), dopamine stabilized a-synuclein oligomers (DO), a-synuclein preformed fibrils (PFF), sonicated a-synuclein preformed fibrils (sPFF), and matured a-synuclein fibrils (Fib). Microglial gene expressions were accessed by transcriptome analysis and Toll-like receptor agonist activities were determined by HEK-Blue TLR reporter assay. Exposures to kinetically stable a-synuclein oligomers and matured a-synuclein fibrils induced the expression of microglial cytokines and chemokines, while other species did not. Microglial transcriptome analysis yielded that all polymorphs commonly induce toll-like receptor (TLR) signaling cascade despite differential transcriptomic phenotypes. Among structurally distinct a-synuclein polymorphs, live cell TLR reporter assay showed that kinetically stable a-synuclein oligomers induce the activities of TLR2 and 4, and sonicated a-synuclein preformed fibril TLR4, relative to the control. These results suggest that structurally distinct a-synuclein polymorphs have likewise distinct neuroinflammatory properties.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305401 | GEO | 2026/01/21

REPOSITORIES: GEO

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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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Differential microglial responses to structurally distinct alpha-synuclein polymorphs

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