title: Mitochondrial defects and neuromuscular degeneration caused by altered expression of Drosophila Gdap1: implications for the Charcot-Marie-Tooth neuropathy.
abstract: One of the genes involved in Charcot-Marie-Tooth (CMT) disease, an inherited peripheral neuropathy, is GDAP1. In this work, we show that there is a true ortholog of this gene in Drosophila, which we have named Gdap1. By up- and down-regulation of Gdap1 in a tissue-specific manner, we show that altering its levels of expression produces changes in mitochondrial size, morphology and distribution, and neuronal and muscular degeneration. Interestingly, muscular degeneration is tissue-autonomous and not dependent on innervation. Metabolic analyses of our experimental genotypes suggest that alterations in oxidative stress are not a primary cause of the neuromuscular degeneration but a long-term consequence of the underlying mitochondrial dysfunction. Our results contribute to a better understanding of the role of mitochondria in CMT disease and pave the way to generate clinically relevant disease models to study the relationship between mitochondrial dynamics and peripheral neurodegeneration.
authors.affiliation: Program of Rare and Genetic Diseases, Centro de Investigación Príncipe Felipe, Valencia, Spain Center for Biomedical Network Research on Rare Diseases (CIBERER), Valencia, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: López Del Amo
authors.affiliation: Center for Biomedical Network Research on Rare Diseases (CIBERER), Valencia, Spain Department of Physiology, School of Medicine and Dentistry, Universitat de València, INCLIVA Biomedical Research Institute, Valencia, Spain and.
authors.forename: Marta
authors.initials: M
authors.lastname: Seco-Cervera
authors.affiliation: Center for Biomedical Network Research on Rare Diseases (CIBERER), Valencia, Spain Department of Physiology, School of Medicine and Dentistry, Universitat de València, INCLIVA Biomedical Research Institute, Valencia, Spain and.
authors.forename: José Luís
authors.initials: JL
authors.lastname: García-Giménez
authors.affiliation: Department of Biomedical Science, University of Sheffield, Sheffield, UK.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Whitworth
authors.affiliation: Center for Biomedical Network Research on Rare Diseases (CIBERER), Valencia, Spain Department of Physiology, School of Medicine and Dentistry, Universitat de València, INCLIVA Biomedical Research Institute, Valencia, Spain and.
authors.forename: Federico V
authors.initials: FV
authors.lastname: Pallardó
authors.affiliation: Program of Rare and Genetic Diseases, Centro de Investigación Príncipe Felipe, Valencia, Spain Center for Biomedical Network Research on Rare Diseases (CIBERER), Valencia, Spain igalindo@cipf.es.
authors.forename: Máximo Ibo
authors.initials: MI
authors.lastname: Galindo
mesh_terms: D000818:Animals; D002607:Charcot-Marie-Tooth Disease; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008928:Mitochondria / Q000502:physiology*; D053142:Mitochondrial Size; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009468:Neuromuscular Diseases / Q000209:etiology* / Q000473:pathology; D010802:Phylogeny; D012160:Retina / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D044783:F-Box Proteins; C533256:Fsn protein, Drosophila; C118663:GDAP protein; D009419:Nerve Tissue Proteins