Glial α-synuclein promotes neurodegeneration characterized by a distinct transcriptional program in vivo

alpha-Synucleinopathies are neurodegenerative diseases that are characterized pathologically by alpha-synuclein inclusions in neurons and glia. The pathologic contribution of glial alpha-synuclein in these diseases is not well understood. Glial alpha-synuclein may be of particular importance in multiple system atrophy (MSA), which is defined pathologically by glial cytoplasmic alpha-synuclein inclusions. We have previously described Drosophila models of neuronal alpha-synucleinopathy, which recapitulate key features of the human disorders. We have now expanded our model to express human alpha-synuclein in glia. We demonstrate that expression of alpha-synuclein in glia alone results in alpha-synuclein aggregation, death of dopaminergic neurons, impaired locomotor function, and autonomic dysfunction. Furthermore, co-expression of alpha-synuclein in both neurons and glia worsens these phenotypes as compared to expression of alpha-synuclein in neurons alone. We identify unique transcriptomic signatures induced by glial as opposed to neuronal alpha-synuclein. These results suggest that glial alpha-synuclein may contribute to the burden of pathology in the alpha-synucleinopathies through a cell type-specific transcriptional program. This new Drosophila model system enables further mechanistic studies dissecting the contribution of glial and neuronal alpha-synuclein in vivo, potentially shedding light on mechanisms of disease that are especially relevant in MSA but also the alpha-synucleinopathies more broadly.