Author(s): Abby L. Olsen, Brigham and Women’s Hospital, Harvard Medical School; Mel B. Feany, Brigham and Women’s Hospital, Harvard Medical School //

ABSTRACT: Idiopathic Parkinson’s disease is the second most common neurodegenerative disease and is estimated to be approximately 30% heritable. Genome wide association studies have revealed numerous loci associated with risk of development of Parkinson’s disease. The majority of genes identified in these studies are expressed in glia at either similar or greater levels than their expression in neurons, suggesting that glia may play a role in Parkinson’s disease pathogenesis. The role of individual glial risk genes in Parkinson’s disease development or progression is unknown, however. We hypothesized that some Parkinson’s disease risk genes exert their effects through glia. We developed a Drosophila model of alpha-synucleinopathy in which we can independently manipulate gene expression in neurons and glia. Human wild type alpha-synuclein is expressed in all neurons, and these flies develop the hallmarks of Parkinson’s disease, including motor impairment, death of dopaminergic and other neurons, and alpha-synuclein aggregation. In these flies, we performed a candidate genetic screen, using RNAi to knockdown 14 well-validated Parkinson’s disease risk genes in glia and measuring the effect on locomotion in order to identify glial modifiers of the alpha-synuclein phenotype. We identified 4 modifiers: aux, Lrrk, Ric, and Vps13, orthologs of the human genes GAK, LRRK2, RIT2, and VPS13C, respectively. Knockdown of each gene exacerbated neurodegeneration as measured by total and dopaminergic neuron loss. Knockdown of each modifier also increased alpha-synuclein oligomerization. These results suggest that some Parkinson’s disease risk genes exert their effects in glia and that glia can influence neuronal alpha-synuclein proteostasis in a non-cell-autonomous fashion. Further, this study provides proof of concept that our novel 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.

Source of Funding: NINDS K08