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

作者：Lopez Del Amo Victor; Seco Cervera Marta; Luis Garcia Gimenez Jose; Whitworth Alexander J; Pallardo Federico V; Ibo Galindo Maximo

来源：Human Molecular Genetics, 2015, 24(1): 21-36.

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.

• 出版日期2015-1-1