To determine the pathologic contribution of glial α-synuclein in α-synucleinopathies 

α-synucleinopathies are neurodegenerative diseases that are characterized pathologically by α-synuclein inclusions in neurons and glia. The role of glia in these diseases is poorly understood, however. Glia may be particularly relevant in multiple system atrophy (MSA), which is defined pathologically by glial cytoplasmic α-synuclein inclusions. The aims of this project are to create a Drosophila model of MSA and more broadly to understand the pathologic contribution of glial α-synuclein to all α-synucleinopathies. 

Using this system we demonstrate that expression of α-synuclein in glia alone induces death of dopaminergic neurons, impairs locomotor function, and worsens constipation. Furthermore, co-expression of α-synuclein in both neurons and glia worsens α-synuclein aggregation compared to expression of α-synuclein in neurons only. Additionally, we present results identifying unique transcriptomic signatures induced by glial as opposed to neuronal α-synuclein.

These results suggest that expression of α-synuclein in glia contributes to the burden of pathology the α-synucleinopathies. They provide the first Drosophila model of MSA, and they identify potential novel glial-specific therapeutic targets for α-synucleinopathies more generally.