A kinome-wide Drosophila RNAi screen identifies glial adenylate kinases as modifiers of neuronal alpha-synuclein toxicity (P5.8-005)

Objective: To identify novel glial modifiers of neuronal α-synuclein toxicity Background: α-synucleinopathies are neurodegenerative diseases that feature both astrogliosis and microgliosis, but the role of glia in these diseases is incompletely understood. Glia have been suggested to be either protective or detrimental depending on their subtype, location, and the stage of disease. We sought to identify glial modifiers of neuronal α-synulcein toxicity in a Drosophila α-synucleinopathy model, in the hopes of finding novel glial-based therapeutic targets for Parkinson’s disease. Design/Methods: The Feany lab has previously characterized a model in which human α-synuclein is expressed in Drosophila neurons using the pan-neuronal driver Syb-QF2. These flies have widespread neurodegeneration, recapitulating human pathology. Using this model, we can independently manipulate gene expression in glia using the glial specific driver, Repo-Gal4. We used this system to knock down the entire Drosophila kinome in glia and assessed the degree of neurodegeneration pathologically and behaviorally. Results: We present results from a kinome-wide RNAi-based screen in glia, which successfully identified multiple enhancers and suppressors of neuronal α-synuclein toxicity. The screen identified kinases previously known to be important for Parkinson’s disease, including Lrrk (Drosophila ortholog of LRRK2), as well as several kinases that have not previously been associated with Parkinson’s disease. We then further characterized a subset of these glial kinases including multiple adenylate kinase family proteins. These proteins control ADP:ATP balance in the cell, and we present mechanistic data demonstrating that manipulation of glial adenylate kinases effects metabolism of the entire brain. This in turn influences behavior and neurodegeneration in a non-cell-autonomous manner. Conclusions: These results demonstrate the utility of Drosophila as a model system for identifying glial modifiers of neuronal α-synuclein toxicity in vivo, and they suggest potential novel glial therapeutic targets for Parkinson’s disease. Disclosure: Dr. Olsen has nothing to disclose. Dr. Feany has nothing to disclose.