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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 critical for mitochondrial integrity in the Drosophila female germline, which may provide a novel context to investigate its functions with parallels to PLAN.

Abstract Since the dawn of the 20th century, the fruit fly Drosophila melanogaster has been used as a model organism to understand the nature of genes and how they control development, behavior, and physiology. One of the most powerful experimental approaches employed in Drosophila is the forward genetic screen. In the 21st century, genome-wide screens have become popular tools for identifying evolutionarily conserved genes involved in complex human diseases. In the accompanying article “Amyotrophic Lateral Sclerosis Modifiers in Drosophila Reveal the  Phospholipase D   Pathway as a Potential Therapeutic Target,” Kankel and colleagues describe a forward genetic modifier screen to discover factors that contribute to the severe neurodegenerative disease amyotrophic lateral sclerosis (ALS). This primer briefly traces the history of genetic screens in Drosophila and introduces students to ALS. We then provide a set of guided reading questions to help students work through the data presented in the research article. Finally, several ideas for literature-based research projects are offered as opportunities for students to expand their appreciation of the potential scope of genetic screens. The primer is intended to help students and instructors thoroughly examine a current study that uses forward genetics in Drosophila to identify human disease genes.

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.sub.2 (iPLA.sub.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.sub.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.sub.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.sub.2 -VIA mRNA expression in adult germ cells, and transgenic HA-tagged iPLA.sub.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.sub.2 -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.

Since the dawn of the 20th century, the fruit fly Drosophila melanogaster has been used as a model organism to understand the nature of genes and how they control development, behavior, and physiology. One of the most powerful experimental approaches employed in Drosophila is the forward genetic screen. In the 21st century, genome-wide screens have become popular tools for identifying evolutionarily conserved genes involved in complex human diseases. In the accompanying article \"Amyotrophic Lateral Sclerosis Modifiers in Drosophila Reveal the Phospholipase D Pathway as a Potential Therapeutic Target,\" Kankel and colleagues describe a forward genetic modifier screen to discover factors that contribute to the severe neurodegenerative disease amyotrophic lateral sclerosis (ALS). This primer briefly traces the history of genetic screens in Drosophila and introduces students to ALS. We then provide a set of guided reading questions to help students work through the data presented in the research article. Finally, several ideas for literature-based research projects are offered as opportunities for students to expand their appreciation of the potential scope of genetic screens. The primer is intended to help students and instructors thoroughly examine a current study that uses forward genetics in Drosophila to identify human disease genes.

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 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 give rise to inherited neurodegenerative diseases including autosomal recessive early onset parkinsonism (PARK14). Using RNAi to deplete the homolog , 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 associated neurodegeneration, we used the well-established climbing assay. Our results demonstrated that loss of in GABAergic neurons alone strongly affected locomotor ability in aged flies, similar to pan-neuronal knockdown. Depletion of 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 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 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.

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 important for germline mitochondrial integrity in Drosophila, which may be relevant for understanding how PLAN develops. Competing Interest Statement The authors have declared no competing interest.