title: A Drosophila model of GDAP1 function reveals the involvement of insulin signalling in the mitochondria-dependent neuromuscular degeneration.
abstract: Charcot-Marie-Tooth disease is a rare peripheral neuropathy for which there is no specific treatment. Some forms of Charcot-Marie-Tooth are due to mutations in the GDAP1 gene. A striking feature of mutations in GDAP1 is that they have a variable clinical manifestation, according to disease onset and progression, histology and mode of inheritance. Studies in cellular and animal models have revealed a role of GDAP1 in mitochondrial morphology and distribution, calcium homeostasis and oxidative stress. To get a better understanding of the disease mechanism we have generated models of over-expression and RNA interference of the Drosophila Gdap1 gene. In order to get an overview about the changes that Gdap1 mutations cause in our disease model, we have combined a comprehensive determination of the metabolic profile in the flies by nuclear magnetic resonance spectroscopy with gene expression analyses and biophysical tests. Our results revealed that both up- and down-regulation of Gdap1 results in an early systemic inactivation of the insulin pathway before the onset of neuromuscular degeneration, followed by an accumulation of carbohydrates and an increase in the β-oxidation of lipids. Our findings are in line with emerging reports of energy metabolism impairments linked to different types of neural pathologies caused by defective mitochondrial function, which is not surprising given the central role of mitochondria in the control of energy metabolism. The relationship of mitochondrial dynamics with metabolism during neurodegeneration opens new avenues to understand the cause of the disease, and for the discovery of new biomarkers and treatments.
authors.affiliation: Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain; Center for Biomedical Network Research on Rare Diseases (CIBERER), 46012 Valencia, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: López Del Amo
authors.affiliation: Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain.
authors.forename: Martina
authors.initials: M
authors.lastname: Palomino-Schätzlein
authors.affiliation: Center for Biomedical Network Research on Rare Diseases (CIBERER), 46012 Valencia, Spain; Department of Physiology, School of Medicine and Dentistry, Universitat de València, INCLIVA Biomedical Research Institute, 46010 Valencia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Seco-Cervera
authors.affiliation: Center for Biomedical Network Research on Rare Diseases (CIBERER), 46012 Valencia, Spain; Department of Physiology, School of Medicine and Dentistry, Universitat de València, INCLIVA Biomedical Research Institute, 46010 Valencia, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: García-Giménez
authors.affiliation: Center for Biomedical Network Research on Rare Diseases (CIBERER), 46012 Valencia, Spain; Department of Physiology, School of Medicine and Dentistry, Universitat de València, INCLIVA Biomedical Research Institute, 46010 Valencia, Spain.
authors.forename: Federico Vicente
authors.initials: FV
authors.lastname: Pallardó
authors.affiliation: Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain; Drug Discovery Unit, Instituto de Investigación Sanitaria La Fe, 46026 Valencia, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pineda-Lucena
authors.affiliation: Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain; IDM-Institute of Molecular Recognition, Universidad Politécnica de Valencia, 46022 Valencia, Spain; UPV-CIPF Joint Unit Disease Mechanisms and Nanomedicine, Valencia, Spain. Electronic address: igalindo@cipf.es.
authors.forename: Máximo Ibo
authors.initials: MI
authors.lastname: Galindo
mesh_terms: D000818:Animals; D050260:Carbohydrate Metabolism; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism; D004330:Drosophila / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D050356:Lipid Metabolism; D055442:Metabolome; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D029721:Drosophila Proteins; C118663:GDAP protein; D007328:Insulin; D009419:Nerve Tissue Proteins
keywords: Charcot-Marie-Tooth; GDAP1; Insulin; Mitochondria