To identify glial genes that influence risk and progression of Parkinson's disease. 

We developed a Drosophila model of alpha-synucleinopathy in which we can manipulate gene expression in neurons and glia independently. Human wild type alpha-synuclein is expressed in neurons, and flies develop the hallmarks of PD. In these flies, we performed a candidate genetic screen, knocking down 14 well-validated PD risk genes in glia and measuring the effect on locomotion in order to identify glial modifiers of the alpha-synuclein phenotype. We then used an array of tools available in Drosophila to identify pathways influenced by the modifiers, including oxidative stress, bioenergetics, proteostasis, and cytoskeleton dysfunction.    

6 out of 14 GWAS candidate genes enhanced the neuronal alpha-synuclein induced motor phenotype when knocked down in glia. 4 of these were selected for further study due to the amplitude of their effect and confirmation with an independent RNAi line: GAK, LRRK2, RIT2, and VPS13C. Knockdown of each gene exacerbated neurodegeneration as measured by total and dopaminergic neuron loss. We identified specific pathways affected by each gene.

These results suggest that some PD risk genes exert their effects at least partially through glia, and they identify specific pathways involved in PD pathogenesis. Further, this study provides proof of concept that our Drosophila alpha-synucleinopathy model can be used to study glial modifier genes, paving the way for future large unbiased screens to identify novel glial risk factors that contribute to PD risk and progression.