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Neuronal identity defines a-synuclein and tau toxicity

ABSTRACT: Pathogenic a-synuclein and tau are critical drivers of neurodegeneration and their mutations cause neuronal loss in patients. Whether the underlying preferential neuronal vulnerability is a cell-type intrinsic property or a consequence of increased expression levels remains elusive. Here, we explore cell-type specific a-synuclein and tau expression in human brain datasets and use deep phenotyping as well as brain- wide single-cell RNA sequencing of >200 live neuron types in fruit flies to ask which cellular environments react most to a-synuclein or tau toxicity. We detect phenotypic and transcriptomic evidence of differential neuronal vulnerability independent of a-synuclein or tau expression levels. Comparing vulnerable with resilient neurons in Drosophila enabled us to predict numerous human neuron subtypes with increased intrinsic susceptibility to pathogenic a-synuclein or tau. By uncovering synapse and Ca2+ homeostasis related genes as tau toxicity modifiers our work paves the way to leverage neuronal identity to uncover modifiers of neurodegeneration-associated toxic proteins.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE223626 | GEO | 2023/03/21

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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Neuronal identity defines a-synuclein and tau toxicity

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