iPLA2-VIA is required for healthy aging in neurons, muscle, and female germline inDrosophila melanogaster

Surya Banerjee, Adina Schonbrun, Sogol Eizadshenass, Shimshon Benji, Yaakov Tzvi Cantor, Liam Eliach, Matthew Lubin, Zev Narrowe, Jeremy Purow, Benjamin Shulman, Leib Wiener, Josefa Steinhauer
2021 · doi:10.1101/2021.04.25.441319
preprint OA: closed
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Abstract

Neurodegenerative disease (ND) is a growing health burden worldwide, but its causes and treatments remain elusive. Although most cases of ND are sporadic, rare familial cases have been attributed to single genes, which can be investigated in animal models. We have generated a new mutation in the calcium-independent phospholipase A 2 (iPLA 2 ) VIA gene CG6718 , the Drosophila melanogaster ortholog of human PLA2G6/PARK14 , mutations in which cause a suite of NDs collectively called PLA2G6 -associated neurodegeneration (PLAN). Our mutants display age-related loss of climbing ability, a symptom of neurodegeneration in flies. Although phospholipase activity commonly is presumed to underlie iPLA 2 -VIA function, locomotor decline in our mutants is rescued by a transgene carrying a serine-to-alanine mutation in the catalytic residue, suggesting that important functional aspects are independent of phospholipase activity. Additionally, we find that iPLA 2 -VIA knockdown in either muscle or neurons phenocopies locomotor decline with age, demonstrating its necessity in both neuronal and non-neuronal tissues. Furthermore, RNA in situ hybridization shows high endogenous iPLA 2 -VIA mRNA expression in adult germ cells, and transgenic HA-tagged iPLA 2 -VIA colocalizes with mitochondria there. Mutant males are fertile with normal spermatogenesis, while fertility is reduced in mutant females. Mutant female germ cells display age-related mitochondrial aggregation, loss of mitochondrial potential, and elevated cell death. These results suggest that iPLA 2 -VIA is important for germline mitochondrial integrity in Drosophila, which may be relevant for understanding how PLAN develops.

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