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Microglia-specific overexpression of alpha-Synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity [single-cell RNA-Seq]

ABSTRACT: Increasing evidence from recent findings in human samples and animal models support the involvement of inflammation in the development of Parkinson’s disease (PD). Nevertheless, it is currently unknown whether microglia activation could also be a primary event leading to neurodegeneration in PD. We have generated a new mouse model with strictly selective alpha-Synuclein (aSYN) accumulation in microglial cells by inducible gene expression through lentiviral transduction in the nigral tissue. Surprisingly, these mice develop progressive and restricted degeneration of dopaminergic (DA) neurons without any sign of aSYN endogenous aggregation. aSYN accumulating microglial cells exhibit a strong inflammatory status with production of pro-inflammatory cytokines and chemokines. Bulk and scRNA-sequencing of the immune cellular infiltrate identify a complex cellular composition with numerous peripheral populations of the innate and adaptive immune system with specific transcriptional signatures. Molecular profiling and functional assessment reveal that intoxicated microglia develop exhausted phagocytosis and high production of oxidative molecules creating a molecular feed-forward vicious cycle with IFNg secreting immune cells infiltrated in the brain parenchyma. In these animals, pharmacological inhibition of the oxidative and nitrosative molecule production is sufficient to attenuate neurodegeneration. These results suggest that aSYN accumulation in microglia exerts selective DA neuronal degeneration by promoting phagocytic exhaustion, excessive toxic environment and selective recruitment of peripheral immune cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE157534 | GEO | 2021/09/13

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.