GABAergic neurons are a key cell type in a Drosophila model of PARK14/PLA2G6-associated neurodegeneration

The causes of sporadic Parkinson's Disease (PD) are still unclear, despite its prevalence. By contrast, inherited parkinsonian disorders have a clear genetic basis and have been studied intensively in laboratory organisms, including <i>Drosophila melanogaster.</i> Because inherited parkinsonian disorders clinically resemble sporadic PD, it has been suggested that they may share an underlying etiology. Loss of function mutations in the gene <i>PLA2G6</i> give rise to inherited neurodegenerative diseases including autosomal recessive early onset parkinsonism (PARK14). Using RNAi to deplete the <i>Drosophila PLA2G6</i> homolog <i>iPLA2-VIA</i>, we asked whether subsets of neurons, identified by their neurotransmitter usage, were more susceptible to loss of this gene. To model movement disorders connected with <i>PLA2G6-</i>associated neurodegeneration, we used the well-established climbing assay. Our results demonstrated that loss of <i>iPLA2-VIA</i> in GABAergic neurons alone strongly affected locomotor ability in aged flies, similar to pan-neuronal knockdown. Depletion of <i>iPLA2-VIA</i> in both dopaminergic and serotonergic neurons weakly affected locomotor ability as well. Depletion in other neuronal subsets did not disrupt locomotion. Furthermore, reintroducing wild-type <i>iPLA2-VIA</i> into only the dopaminergic neurons of fly knockouts improved climbing performance slightly, while reintroduction into GABAergic neurons rescued climbing performance strikingly, as well as lifespan. Although much research on this gene has focused on the dopaminergic neurons, whose degeneration leads to clinical parkinsonism, our results highlight the importance of GABAergic neurons to <i>PLA2G6-</i>associated neurodegeneration. Because sporadic PD is not thought to impact most GABAergic neurons directly, our data support the idea that sporadic PD and PARK14 have distinct etiologies despite overlapping clinical presentations.