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A new metabolic model of Drosophila melanogaster and the integrative analysis of Parkinson’s disease

ABSTRACT: The reconstruction of a comprehensive and literature-curated Drosophila metabolic model, iDrosophila1, provided a powerful platform for studying metabolism with systems medicine perspective. High conservation of the disease-associated genes between flies and humans facilitates the common use of Drosophila melanogaster to study metabolic disorders under controlled laboratory conditions. However, metabolic modeling studies are highly limited for this organism. We here report a comprehensively curated genome-scale metabolic network model of Drosophila using an orthology-based approach. The gene coverage and metabolic information of the draft model derived from a reference human model were expanded via Drosophila-specific KEGG and MetaCyc databases, with several curation steps to avoid metabolic redundancy and stoichiometric inconsistency. Furthermore, we performed literature-based curations to improve gene–reaction associations, subcellular metabolite locations, and various metabolic pathways. The performance of the resulting Drosophila model (8,230 reactions, 6,990 metabolites, and 2,388 genes), iDrosophila1 (https://github.com/SysBioGTU/iDrosophila), was assessed using flux balance analysis in comparison with the other currently available fly models leading to superior or comparable results. We also evaluated the transcriptome-based prediction capacity of iDrosophila1, where differential metabolic pathways during Parkinson’s disease could be successfully elucidated. Overall, iDrosophila1 is promising to investigate system-level metabolic alterations in response to genetic and environmental perturbations.

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PROVIDER: S-EPMC10215973 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Project description:Aging is commonly described as being a continuous process affecting progressively organisms as time passes. This process results in a progressive decrease in individuals fitness through a wide range of both organismal-decreased motor activity, fertility, resistance to stress-and molecular phenotypes-decreased protein and energy homeostasis, impairment of insulin signaling. In the past 20 years, numerous genes have been identified as playing a major role in the aging process, yet little is known about the events leading to that loss of fitness. We recently described an event characterized by a dramatic increase of intestinal permeability to a blue food dye in aging flies committed to die within a few days. Importantly, flies showing this so called 'Smurf' phenotype are the only ones, among a population, to show various age-related changes and exhibit a high-risk of impending death whatever their chronological age. Thus, these observations suggest that instead of being one continuous phenomenon, aging may be a discontinuous process well described by at least two distinguishable phases. In this paper we addressed this hypothesis by implementing a new 2 Phases of Aging mathematiCal model (2PAC model) to simulate longevity curves based on the simple hypothesis of two consecutive phases of lifetime presenting different properties. We first present a unique equation for each phase and discuss the biological significance of the 3 associated parameters. Then we evaluate the influence of each parameter on the shape of survival curves. Overall, this new mathematical model, based on simple biological observations, is able to reproduce many experimental longevity curves, supporting the existence of 2 phases of aging exhibiting specific properties and separated by a dramatic transition that remains to be characterized. Moreover, it indicates that Smurf survival can be approximated by one single constant parameter for a broad range of genotypes that we have tested under our environmental conditions.

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A new metabolic model of Drosophila melanogaster and the integrative analysis of Parkinson’s disease

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