TDP-43 and FUS: a nuclear affair

Trends Neurosci. 2011 Jul;34(7):339-48. doi: 10.1016/j.tins.2011.05.002. Epub 2011 Jun 22.

Abstract

Misfolded TAR DNA binding protein 43 (TDP-43) and Fused-In-Sarcoma (FUS) protein have recently been identified as pathological hallmarks of the neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) characterized by the presence of ubiquitin-positive inclusions (FTLD-U). Although TDP-43 and FUS are normally located predominantly in the nucleus, pathological TDP-43 and FUS inclusions are mostly found in the cytosol. Cytosolic deposition is paralleled by a striking nuclear depletion of either protein. Based on a number of recent findings, we postulate that defects in nuclear import are an important step towards TDP-43 and FUS dysfunction. Failure of nuclear transport can arise from mutations within a nuclear localization signal or from age-related decline of nuclear import mechanisms. We propose that nuclear import defects in combination with additional hits, for example cellular stress and genetic risk factors, may be a central underlying cause of ALS and FTLD-U pathology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / physiology
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Cell Nucleus / metabolism*
  • Cell Nucleus / pathology*
  • DNA-Binding Proteins / metabolism*
  • Frontotemporal Lobar Degeneration / metabolism*
  • Frontotemporal Lobar Degeneration / pathology
  • Humans
  • Inclusion Bodies / metabolism
  • Inclusion Bodies / pathology
  • Protein Transport / physiology
  • RNA-Binding Protein FUS / metabolism*

Substances

  • DNA-Binding Proteins
  • RNA-Binding Protein FUS