Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD

Sci Rep. 2016 Feb 12:6:20877. doi: 10.1038/srep20877.

Abstract

Hexanucleotide repeat expansions in C9orf72 are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) (c9ALS/FTD). Unconventional translation of these repeats produces dipeptide repeat proteins (DPRs) that may cause neurodegeneration. We performed a modifier screen in Drosophila and discovered a critical role for importins and exportins, Ran-GTP cycle regulators, nuclear pore components, and arginine methylases in mediating DPR toxicity. These findings provide evidence for an important role for nucleocytoplasmic transport in the pathogenic mechanism of c9ALS/FTD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / genetics
  • Amyotrophic Lateral Sclerosis / genetics*
  • Animals
  • Arginine / metabolism
  • Cell Nucleus / metabolism*
  • Dipeptides / chemistry*
  • Disease Models, Animal
  • Drosophila melanogaster / genetics*
  • Eye / pathology
  • Frontotemporal Dementia / genetics*
  • Genes, Insect*
  • Genetic Testing*
  • HeLa Cells
  • Humans
  • Methylation
  • RNA Interference
  • Repetitive Sequences, Amino Acid*

Substances

  • Dipeptides
  • Arginine