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

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

SUBMITTER: Olsen AL 

PROVIDER: S-EPMC7212549 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature