Mitochondrial defects and neuromuscular degeneration caused by altered expression of Drosophila Gdap1: implications for the Charcot-Marie-Tooth neuropathy

• Published in: Human molecular genetics 2015-01, Vol.24 (1), p.21-36
• Main Authors: López Del Amo, Víctor, Seco-Cervera, Marta, García-Giménez, José Luís, Whitworth, Alexander J, Pallardó, Federico V, Galindo, Máximo Ibo
• Format: Article
• Language: English
• Subjects: Animals; Charcot-Marie-Tooth Disease; Disease Models, Animal; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; F-Box Proteins - genetics; F-Box Proteins - metabolism; Gene Expression Regulation; Humans; Mitochondria - physiology; Mitochondrial Size; Nerve Tissue Proteins - metabolism; Neuromuscular Diseases - etiology; Neuromuscular Diseases - pathology; Phylogeny; Retina - metabolism
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddu416

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.