FET proteins in frontotemporal dementia and amyotrophic lateral sclerosis

Brain Res. 2012 Jun 26;1462:40-3. doi: 10.1016/j.brainres.2011.12.010. Epub 2011 Dec 13.

Abstract

Mutations in the fused in sarcoma gene (FUS) cause amyotrophic lateral sclerosis (ALS) with TDP-43-negative, FUS-positive pathology. FUS is also the pathological protein in most tau/TDP-43-negative subtypes of frontotemporal lobar degeneration (FTLD-FUS). FUS, together with Ewing's sarcoma protein (EWS) and TATA-binding protein associated factor 15 (TAF15), make up the FET family of DNA/RNA binding proteins that share functional homology and have the potential to interact. We recently investigated the role of the other FET proteins in the clinicopathological spectrum of FUS-opathies. In all FTLD-FUS subtypes, FUS-positive pathology was also labeled for TAF15 and EWS and cells with inclusions showed a reduction in the normal nuclear staining of all FET proteins. In contrast, in cases of ALS-FUS, TAF15 and EWS remained localized to the nucleus and did not label FUS-positive inclusions. Cell culture models replicated the human diseases. These findings indicate that ALS-FUS and FTLD-FUS have different pathomechanisms and add TAF15 and EWS to the growing list of RNA-binding proteins involved in neurodegeneration. This article is part of a Special Issue entitled: RNA-Binding Proteins.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Frontotemporal Lobar Degeneration / genetics*
  • Humans
  • Inclusion Bodies / genetics
  • Inclusion Bodies / metabolism
  • RNA-Binding Protein EWS / genetics
  • RNA-Binding Protein FUS / genetics
  • RNA-Binding Protein FUS / metabolism
  • RNA-Binding Proteins / metabolism*
  • TATA-Binding Protein Associated Factors / genetics
  • TATA-Binding Protein Associated Factors / metabolism
  • TDP-43 Proteinopathies / genetics
  • tau Proteins / genetics

Substances

  • RNA-Binding Protein EWS
  • RNA-Binding Protein FUS
  • RNA-Binding Proteins
  • TAF15 protein, human
  • TATA-Binding Protein Associated Factors
  • tau Proteins