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

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