RNA binding mediates neurotoxicity in the transgenic Drosophila model of TDP-43 proteinopathy

Hum Mol Genet. 2013 Nov 15;22(22):4474-84. doi: 10.1093/hmg/ddt296. Epub 2013 Jun 25.

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive and selective loss of motor neurons. The discovery of mutations in the gene encoding an RNA-binding protein, TAR DNA-binding protein of 43 kD (TDP-43), in familial ALS, strongly implicated abnormalities in RNA processing in the pathogenesis of ALS, although the mechanisms whereby TDP-43 leads to neurodegeneration remain elusive. To clarify the mechanism of degeneration caused by TDP-43, we generated transgenic Drosophila melanogaster expressing a series of systematically modified human TDP-43 genes in the retinal photoreceptor neurons. Overexpression of wild-type TDP-43 resulted in vacuolar degeneration of the photoreceptor neurons associated with thinning of the retina, which was significantly exacerbated by mutations of TDP-43 linked to familial ALS or disrupting its nuclear localization signal (NLS). Remarkably, these degenerative phenotypes were completely normalized by addition of a mutation or deletion of the RNA recognition motif that abolishes the RNA binding ability of TDP-43. Altogether, our results suggest that RNA binding is key to the neurodegeneration caused by overexpression of TDP-43, and that abnormalities in RNA processing may be crucial to the pathogenesis of TDP-43 proteinopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Animals, Genetically Modified
  • Binding Sites
  • Cytosol / metabolism
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Disease Models, Animal
  • Drosophila melanogaster / genetics*
  • Drosophila melanogaster / metabolism
  • Humans
  • Nerve Degeneration
  • Phenotype
  • Photoreceptor Cells, Invertebrate / metabolism
  • Photoreceptor Cells, Invertebrate / pathology
  • RNA / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Retinal Degeneration / genetics
  • Retinal Degeneration / metabolism
  • Retinal Degeneration / pathology
  • TDP-43 Proteinopathies / genetics
  • TDP-43 Proteinopathies / metabolism
  • TDP-43 Proteinopathies / pathology*

Substances

  • DNA-Binding Proteins
  • RNA-Binding Proteins
  • RNA