View Program - 63rd Annual Drosophila Research Conference

Neurodegenerative disease (ND) is a major health issue world-wide, yet the underlying mechanisms are still ill-defined. Loss of function mutations in the gene PLA2G6, encoding the group 6A calcium-independent phospholipase A₂, iPLA2-VIA, are associated with severe ND in humans, including autosomal recessive dystonia-parkinsonism. The orthologous Drosophila melanogaster gene encodes a highly similar protein to the human gene product, and loss of function mutations in flies lead to neuron loss and age-dependent locomotor defects. We have discovered a novel role for iPLA2-VIA in the Drosophila female germline. In wild-type flies, iPLA2-VIA is highly expressed in adult germ cells, and a transgenic HA-tagged iPLA2-VIA protein (PB isoform) localizes to the mitochondria of nurse cells. Furthermore, a null mutation in iPLA2-VIA, generated in our lab, causes age-related mitochondrial aggregation and loss of mitochondrial membrane potential in the female germline, symptoms of mitochondrial damage, with eventual germ cell apoptosis. The mitochondrial localization of the protein and the cellular effects in the mutant mirror the behavior of this gene in neurons, suggesting possible common underlying mechanisms of action in these two cell types. Because iPLA2-VIA is expressed broadly in somatic tissues as well as in germ cells, we explored the tissue autonomy of the germline mitochondrial defects using our technique to quantitatively analyze nurse cell mitochondrial aggregation. Surprisingly, germline iPLA2-VIA RNAi knockdown only mildly phenocopied the null mutation, while ubiquitous somatic knockdown led to strong mitochondrial aggregation and death of female germ cells, suggesting a strong non-autonomous component to the germline mitochondrial defects. We currently are knocking down iPLA2-VIA in select somatic tissues, including neurons, muscle, fat body, and ovarian follicle cells, to determine which specific tissues contribute to the germ cell phenotype. In complementary studies, we are conducting tissue-specific rescue experiments using a wild-type cDNA transgene or a catalytically-inactive cDNA transgene, both of which rescue age-dependent locomotor decline. Finally, we have shown that iPLA2-VIA does not interact genetically with pink1, another neurodegeneration gene important for germline mitochondrial integrity, suggesting parallel pathways. We expect our findings to have relevance to the mechanisms underlying PLA2-associated neurodegeneration.

The neurodegeneration gene iPLA2-VIA is required for mitochondrial maintenance in the Drosophila melanogaster female germline, with autonomous and non-autonomous components

**The neurodegeneration gene iPLA2-VIA is required for mitochondrial maintenance in the Drosophila melanogaster female germline, with autonomous and non-autonomous components**