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

Hum Mol Genet. 2015 Jan 1;24(1):21-36. doi: 10.1093/hmg/ddu416. Epub 2014 Aug 13.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Charcot-Marie-Tooth Disease
  • Disease Models, Animal
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / 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


  • Drosophila Proteins
  • F-Box Proteins
  • Fsn protein, Drosophila
  • GDAP protein
  • Nerve Tissue Proteins