Abstract
The human PAPLA1 phospholipase family is associated with hereditary spastic paraplegia (HSP), a neurodegenerative syndrome characterized by progressive spasticity and weakness of the lower limbs. Taking advantage of a new Drosophila PAPLA1 mutant, we describe here novel functions of this phospholipase family in fly development, reproduction, and energy metabolism. Loss of Drosophila PAPLA1 reduces egg hatchability, pre-adult viability, developmental speed, and impairs reproductive functions of both males and females. In addition, our work describes novel metabolic roles of PAPLA1, manifested as decreased food intake, lower energy expenditure, and reduced ATP levels of the mutants. Moreover, PAPLA1 has an important role in the glycogen metabolism, being required for expression of several regulators of carbohydrate metabolism and for glycogen storage. In contrast, global loss of PAPLA1 does not affect fat reserves in adult flies. Interestingly, several of the PAPLA1 phenotypes in fly are reminiscent of symptoms described in some HSP patients, suggesting evolutionary conserved functions of PAPLA1 family in the affected processes. Altogether, this work reveals novel physiological functions of PAPLA1, which are likely evolutionary conserved from flies to humans.
Highlights
Degeneration of the pyramidal tract axon[7,9]
This study aimed to investigate PAPLA1 functions using the Drosophila model, which has only a single member of this family, and is free of any confounding effects of redundancy that might occur in the mammals
Taking advantage of this model system we show that PAPLA1 is required for a broad range of functions, from early development to energy storage
Summary
Degeneration of the pyramidal tract axon[7,9]. Onset of this degeneration varies; early onset is often associated with mild progression without the need for wheelchair assistance. Understanding of the developmental and metabolic consequences of iPLAs deficiencies in human patients is hampered by various limitations including the low frequency of the disease, the variable penetrance and expressivity of the associated symptoms, and the confounding effects of the altered lifestyle of the patient. Given the plethora of signals that are transduced by GPCRs24,25, loss of PAPLA1 can be expected to severely affect fly physiology, including developmental and metabolic roles. We reasoned that implementation of Drosophila as a model for human diseases caused by defective iPLA1s requires a general understanding of the physiological and metabolic consequences of PAPLA1 deficiency. Using Drosophila as a model system, we describe the broad developmental and metabolism-related role of this enzyme, which might be present, but due to the gene redundancy partially masked in the mammalian family of PAPLA1 enzymes
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