TDP-43 loss-of-function causes neuronal loss due to defective steroid receptor-mediated gene program switching in Drosophila

Cell Rep. 2013 Jan 31;3(1):160-72. doi: 10.1016/j.celrep.2012.12.014. Epub 2013 Jan 17.


TDP-43 proteinopathy is strongly implicated in the pathogenesis of amyotrophic lateral sclerosis and related neurodegenerative disorders. Whether TDP-43 neurotoxicity is caused by a novel toxic gain-of-function mechanism of the aggregates or by a loss of its normal function is unknown. We increased and decreased expression of TDP-43 (dTDP-43) in Drosophila. Although upregulation of dTDP-43 induced neuronal ubiquitin and dTDP-43-positive inclusions, both up- and downregulated dTDP-43 resulted in selective apoptosis of bursicon neurons and highly similar transcriptome alterations at the pupal-adult transition. Gene network analysis and genetic validation showed that both up- and downregulated dTDP-43 directly and dramatically increased the expression of the neuronal microtubule-associated protein Map205, resulting in cytoplasmic accumulations of the ecdysteroid receptor (EcR) and a failure to switch EcR-dependent gene programs from a pupal to adult pattern. We propose that dTDP-43 neurotoxicity is caused by a loss of its normal function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Animals
  • Apoptosis / genetics
  • Base Sequence
  • Cell Lineage / genetics
  • Cell Shape
  • DNA-Binding Proteins / metabolism*
  • Drosophila melanogaster / cytology*
  • Drosophila melanogaster / genetics*
  • Drosophila melanogaster / growth & development
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Gene Knockdown Techniques
  • Gene Regulatory Networks / genetics
  • Genes, Switch*
  • Genotype
  • Humans
  • Invertebrate Hormones / metabolism
  • Metamorphosis, Biological / genetics
  • Mice
  • Molecular Sequence Data
  • Neurons / metabolism*
  • Neurons / pathology*
  • Phenotype
  • Protein Transport
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Steroid / metabolism*
  • Transcriptome / genetics
  • Wings, Animal / cytology
  • Wings, Animal / growth & development


  • DNA-Binding Proteins
  • Invertebrate Hormones
  • RNA, Messenger
  • Receptors, Steroid
  • ecdysone receptor
  • bursicon

Associated data

  • GEO/GSE42844