Identifying potential dietary treatments for inherited metabolic disorders using Drosophila nutrigenomics
Felipe Martelli,
Jiayi Lin,
Sarah Mele,
Wendy Imlach,
Oguz Kanca,
Christopher K. Barlow,
Jefferson Paril,
Ralf B. Schittenhelm,
John Christodoulou,
Hugo J. Bellen,
Matthew D.W. Piper,
Travis K. Johnson
Affiliations
Felipe Martelli
School of Biological Sciences, Monash University, Clayton, VIC 3800, Australia
Jiayi Lin
School of Biological Sciences, Monash University, Clayton, VIC 3800, Australia
Sarah Mele
School of Biological Sciences, Monash University, Clayton, VIC 3800, Australia
Wendy Imlach
Department of Physiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
Oguz Kanca
Department of Molecular and Human Genetics and Duncan Neurological Research Institute at Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA
Christopher K. Barlow
Monash Proteomics & Metabolomics Facility, Monash Biomedicine Discovery Institute & Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia
Jefferson Paril
School of BioSciences, The University of Melbourne, Melbourne, VIC 3052, Australia
Ralf B. Schittenhelm
Monash Proteomics & Metabolomics Facility, Monash Biomedicine Discovery Institute & Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia
John Christodoulou
Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, The University of Melbourne, Melbourne, VIC 3052, Australia
Hugo J. Bellen
Department of Molecular and Human Genetics and Duncan Neurological Research Institute at Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA
Matthew D.W. Piper
School of Biological Sciences, Monash University, Clayton, VIC 3800, Australia; Corresponding author
Travis K. Johnson
School of Biological Sciences, Monash University, Clayton, VIC 3800, Australia; Department of Biochemistry and Chemistry and La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3086, Australia; Corresponding author
Summary: Inherited metabolic disorders are a group of genetic conditions that can cause severe neurological impairment and child mortality. Uniquely, these disorders respond to dietary treatment; however, this option remains largely unexplored because of low disorder prevalence and the lack of a suitable paradigm for testing diets. Here, we screened 35 Drosophila amino acid disorder models for disease-diet interactions and found 26 with diet-altered development and/or survival. Using a targeted multi-nutrient array, we examine the interaction in a model of isolated sulfite oxidase deficiency, an infant-lethal disorder. We show that dietary cysteine depletion normalizes their metabolic profile and rescues development, neurophysiology, behavior, and lifelong fly survival, thus providing a basis for further study into the pathogenic mechanisms involved in this disorder. Our work highlights the diet-sensitive nature of metabolic disorders and establishes Drosophila as a valuable tool for nutrigenomic studies for informing potential dietary therapies.
