IPLA2-VIA is required for healthy aging of neurons, muscle, and the female germline in Drosophila melanogaster.

Surya Jyoti Banerjee,Benjamin Shulman,Yaakov Tzvi Cantor,Josefa Steinhauer,Jeremy Purow,Sogol Eizadshenass,Matthew Lubin,Liam Eliach,Shimshon Benji,Zev Narrowe,Adina Schonbrun,Leib Wiener,Subhabrata Sanyal

doi:10.1371/journal.pone.0256738

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 A2 (iPLA2) 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 iPLA2-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 iPLA2-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 iPLA2-VIA mRNA expression in adult germ cells, and transgenic HA-tagged iPLA2-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 iPLA2-VIA is critical for mitochondrial integrity in the Drosophila female germline, which may provide a novel context to investigate its functions with parallels to PLAN.

Highlights

As global population demographics have shifted toward older age, neurodegenerative disease (ND) has become an increasing health burden worldwide [1]
Reverse transcription (RT)—PCR confirmed the absence of full-length independent phospholipase A2 (iPLA2)-VIA mRNA in our mutant, while the EY5103 insertion line retains a low level of iPLA2-VIA transcript (Fig 1C, see [36])
We tested for genetic interactions between our iPLA2-VIAΔ23 mutation and a pcyt1 loss of function allele that reduces PC levels [42], reasoning that removing iPLA2-VIA from the pcyt1 mutant might partially suppress its phenotype by allowing more PC to accumulate

Summary

Introduction

As global population demographics have shifted toward older age, neurodegenerative disease (ND) has become an increasing health burden worldwide [1]. Parkinson’s disease is the second most common ND, affecting ~1% of individuals over the age of 60 [3]. Most cases of Parkinson’s disease are sporadic, presumably arising from a complex interplay between genotype and environment. Though, environmental toxins have been identified as direct causative agents. The herbicide paraquat and the pesticide rotenone have been linked to the disease [5, 6]. These toxins inhibit the electron transport chain and promote oxidative stress, suggesting that mitochondrial dysfunction is central, and potentially causative in some cases, to the disease pathology [7, 8]

Methods

Results

Conclusion